Genes associated with progression and response in chronic myeloid leukemia and uses thereof

ABSTRACT

The invention provides molecular markers that are associated with the progression of chronic myeloid leukemia (CML), and methods and computer systems for monitoring the progression of CML in a patient based on measurements of these molecular markers. The present invention also provides CML target genes, and methods and compositions for treating CML patients by modulating the expression or activity of these CML target genes and/or their encoded proteins. The invention also provides genes that are associated with resistance to imatinib mesylate (Gleevec™) treatment in CML patients, and methods and compositions for determining the responsiveness of a CML patient to imatinib mesylate treatment based on measurements of these genes and/or their encoded proteins. The invention also provides methods and compositions for enhancing the effect of Gleevec™ by modulating the expression or activity of these genes and/or their encoded proteins.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/640,517 filed Dec. 14, 2006 which claims the benefit, under 35 U.S.C.§19(e), of U.S. Provisional Patent Application No. 60/751,455, filed onDec. 15, 2005. Each of which is incorporated herein by reference in itsentirety.

This invention was made with U.S. Government support under Contract Nos.CA-18029 and CA-85053 awarded by the National Institutes of Health ofthe United States Department of Health and Human Services. The U.S.Government has certain rights in the invention.

This application includes the Sequence Listing submitted in the parentapplication, entitled “Genes Associated with Progression and Response inChronic Myeloid Leukemia and Uses Thereof” Ser. No. 11/640,517, filedDec. 14, 2006, which is hereby incorporated by reference herein in itsentirety.

TECHNICAL FIELD

The invention relates to molecular markers that are associated with theprogression of chronic myeloid leukemia (CML). The invention alsorelates to methods and computer systems for evaluating the progressionof CML based on these molecular markers. The present invention alsorelates to methods and compositions for treating CML patients bymodulating the expression or activity of certain genes involved in CMLprogression and/or their encoded proteins. The invention further relatesto methods and compositions for determining the responsiveness of a CMLpatient to imatinib mesylate (Gleevec™)

BACKGROUND

Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease withdistinct biological and clinical features. In humans, a majority of CML(about 95%) has been found to be associated with a chromosomalabnormality that involves a t(9;22)(q34;q11) translocation, whichresults in the expression of the BCR/ABL fusion gene (PhiladelphiaChromosome or Ph). The rest is associated with either a cryptictranslocation that is invisible on G-banded chromosome preparations or avariant translocation involving another chromosome or chromosomes aswell as chromosomes 9 and 22. CML usually presents in the so-calledchronic phase, in which the clonal expansion of mature myeloid cellsleads to an elevated white blood cell (WBC) count. Without curativeintervention chronic phase CML will invariably transform through a phaseof “acceleration,” often heralded by the appearance of increasedimmature myeloid cells in the bone marrow and peripheral blood, as wellas new cytogenetic changes in addition to the Ph chromosome. Progressionthen proceeds quickly to blast crisis, with immature blast cellsoverwhelming the production of normal hematopoetic elements. Blastcrisis is highly resistant to treatment, with death generally occurringfrom infection and bleeding complications secondary to the absence ofnormal granulocytes and platelets. The median time from diagnosis ofchronic phase CML to progression blast crisis is approximately 3-4 yearsbut the range of timing is quite broad, encompassing from 0.5-15 years(Faderl et al., 1999, Ann Intern Med 131:207).

There is a broad range of treatment options for CML. All treatments workfar better on chronic phase disease than on accelerated or blast phase.The only known curative therapy for CML is stem cell transplantation, acomplex and potentially toxic modality that carries a high potential formorbidity and mortality (Radich et al., 2003, Blood 102:31).Non-transplant therapy includes alpha interferon, which can produce amajor reduction in the proportion of Ph positive cells and extend thenatural history of the disease in approximately 10-20% of cases(Kantarjian et al., 1999, J Clin Oncol 17:284). The tyrosine kinaseinhibitor, imatinib mesylate, suppresses the Ph to the point where it isundetectable by cytogenetic evaluation (“complete cytogeneticremission”) in >70% of newly diagnosed chronic phase CML cases (Drukeret al., 2001, N Engl J Med 344:1031). The duration of such responses isunknown, as is potential for cure with imatinib. Resistance to imatiniboccurs (especially in advanced phase disease) often accompanied by pointmutations in the active area of imatinib binding in the abl gene (Shahet al., 2002, Cancer Cell 2:117). The natural history of such relapsesis unknown, though some appear to have a speedy entry into advanceddisease (Branford et al., 2003, Blood 102:276).

U.S. Patent Application Publication No. 2003/0104426 A1 disclosesgenetic markers whose expression correlates with progression of CML.Specifically, the patent application discloses sets of markers whoseexpression patterns can be used to differentiate chronic phaseindividuals from those in blast crisis, and methods of using thesemarkers to distinguish these conditions. The patent application alsodiscloses kits containing ready-to-use microarrays and computer dataanalysis software for carrying out the disclosed methods.

PRAME (Preferentially Expressed Antigen of Melanoma) was identified as atumor antigen recognized by cytotoxic T-cells against a melanoma surfaceantigen (Matsushita et al., 2001, Br J Haematol 112:916, 2001; van Barenet al., 1998, Br J Haematol 102:1376). PRAME has been found to beoverexpressed in over 25% of leukemia, and has been found to be inducedby Bcr-Abl in CML cell lines (Watari et al., 2000, FEBS Lett 466:367).PRAME over-expression has been described as one of the few features thatcharacterize the transient myeloproliferative syndrome of Down'ssyndrome from the progressive acute megakaryoblastic leukemia found inthat disorder (McElwaine et al., 2004, Br J Haematol 125:729).

The genetic events that cause the progression of chronic phase to blastcrisis CML are unknown (Calabretta et al., 2004, Blood 103:4010; Shet etal., 2002, Leukemia 16:1402). Numerous genetic abnormalities have beendemonstrated, including chromosomal changes including a multiplicationof the Ph, the disruption of TP53, the deletion of the p15/p16 tumorsuppressor genes (the latter only in lymphoid blast crisis). However,none of these changes are particularly common. Genetic instability isapparent in the additional chromosomal changes that occur withprogression, though standard assays of instability, such as alterationsin minisatellite repeats, is relatively uncommon (Wada et al., 1994,Blood 83:3449; Mori et al., 1997, Leukemia 11:151). Unfortunately,clinical and molecular tests cannot predict where on the “clock” ofprogression an individual lies at the time of the initial diagnosis, andthis makes it impossible to tailor therapy to the degree of risk thatfaces an individual CML patient. It is also not possible to identify thesubset of patients who will benefit most from the variety of therapyoptions, such as interferon, imatinib, or transplantation. Thus,presently tailoring therapy to individual risk is difficult. There istherefore a need to identify genes whose levels of expression changeduring the evolution of the chronic phase to blast crisis. There is aneed for methods that utilize measured expression levels of such genesto determine the phase and/or progression of CML in a patient. There isalso a need for methods of treating CML by targeting such genes.

Discussion or citation of a reference herein shall not be construed asan admission that such reference is prior art to the present invention.

SUMMARY

The invention provides a method for determining the progression ofchronic myeloid leukemia (CML) in a patient, comprising (a) classifyinga marker profile comprising measurements of a plurality of gene productsin a cell sample taken from said patient as a chronic phase (CP-CML)profile or as an advanced phase (ADV-CML) profile, wherein said geneproducts are respectively products of at least 5 of the genes listed inTable 1a and/or Table 1b or respective functional equivalents thereof,wherein at least one of said 5 genes is from Table 1a; and (b)determining said patient as in a chronic phase if said marker profile isclassified as a CP-CML profile, or determining said patient as in anadvanced phase if said marker profile is classified as an ADV-CMLprofile. In one embodiment, said plurality of gene products are of atleast 5, 10, 20, 50, 70 or 100 of the genes listed in Table 1a. In oneembodiment, said cell sample is a bone marrow sample or a peripheralblood sample.

In one embodiment, the method further comprises obtaining said markerprofile by a method comprising measuring said plurality of gene productsin a cell sample taken from said patient.

In preferred embodiments, said gene products are products of at least10, at least 20, at least 40, at least 70, at least 100, or at least 500of the genes, respectively, listed in Table 1a and/or 1b.

In another preferred embodiment, said gene products are products of atleast 10, at least 20, at least 40, at least 70, at least 100, or atleast 200 of the genes, respectively, listed in Table 2a.

In still another preferred embodiment, said gene products are productsof at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or allof the genes, respectively, corresponding to the markers listed in Table3. In one embodiment, said gene products are products of at least 5, 6,7, 8, 9 or all of the genes, respectively, corresponding to theup-regulated markers listed in Table 3, or are products of at least 5,6, 7, 8, 9 or all of the genes, respectively, corresponding to thedown-regulated markers listed in Table 3.

In one embodiment, each of said gene products is a gene transcript.

In one embodiment, measurement of each said gene transcript is obtainedby a method comprising contacting a positionally-addressable microarraywith nucleic acids from said cell sample or nucleic acids derivedtherefrom under hybridization conditions, and detecting the amount ofhybridization that occurs, said microarray comprising one or morepolynucleotide probes complementary to a hybridizable sequence of eachsaid gene transcript.

In another embodiment, measurement of each said gene transcript isobtained by quantitative reverse transcriptase PCR (qRT-PCR).

In another embodiment, each of said plurality of gene products is aprotein.

In a preferred embodiment, said classifying is carried out using aprogression classifier, which receives an input comprising said markerprofile and provides an output comprising data indicating whether saidmarker profile is a CP-CML profile or an ADV-CML profile.

In one embodiment, said progression classifier is trained with trainingdata from a plurality of training CML patients, wherein said trainingdata comprise for each of said plurality of training CML patients (i) atraining maker profile comprising measurements of said plurality of geneproducts in a cell sample taken from said training patient; and (ii)data indicating whether said training patient is in CP-CML or ADV-CML.

In a preferred embodiment, said progression classifier comprises aCP-CML template comprising measurements of said plurality of geneproducts representative of measurements of said plurality of genesproducts in a plurality of patients having CP-CML and/or an ADV-CMLtemplate comprising measurements of said plurality of gene productsrepresentative of measurements of said plurality of genes products in aplurality of patients having ADV-CML, and said step of classifying iscarried out by a method comprising (i) comparing said marker profilewith said CP-CML template and/or said ADV-CML template; and (ii)classifying said marker profile as a CP-CML profile if said markerprofile has a high similarity to said CP-CML template and/or has a lowsimilarity to said ADV-CML template, or classifying said marker profileas a ADV-CML profile if said marker profile has a high similarity tosaid ADV-CML template and/or has a low similarity to said CP-CMLtemplate, wherein a high similarity corresponds to a degree ofsimilarity above a predetermined threshold, and wherein a low similaritycorresponds to a degree of similarity no greater than said predeterminedthreshold.

In a specific embodiment, said step of classifying is carried out by amethod comprising (i) comparing said marker profile with said CP-CMLtemplate or said ADV-CML template; and (ii) classifying said markerprofile as a CP-CML profile if said marker profile has a high similarityto said CP-CML template or has a low similarity to said ADV-CMLtemplate, or classifying said marker profile as a ADV-CML profile ifsaid marker profile has a high similarity to said ADV-CML template orhas a low similarity to said CP-CML template, wherein a high similaritycorresponds to a degree of similarity above a predetermined threshold,and wherein a low similarity corresponds to a degree of similarity nogreater than said predetermined threshold.

In another specific embodiment, said step of classifying is carried outby a method comprising (i) comparing said marker profile with saidCP-CML template and said ADV-CML template; and (ii) classifying saidmarker profile as a CP-CML profile if said marker profile has a highersimilarity to said CP-CML template than to said ADV-CML template, orclassifying said marker profile as a ADV-CML profile if said markerprofile has a higher similarity to said ADV-CML template than to saidCP-CML template.

In one embodiment, said similarity to said CP-CML template isrepresented by a correlation coefficient between said marker profile andsaid CP-CML template, wherein said similarity to said ADV-CML templateis represented by a correlation coefficient between said marker profileand said ADV-CML template. In one embodiment, said correlationcoefficients between said marker profile and said CP-CML template andsaid ADV-CML template are respectively calculated according to theequation

P _(i)=({right arrow over (z)} _(i) ·{right arrow over (y)})/(∥{rightarrow over (z)} _(i) ∥·∥{right arrow over (y)}∥)

where i=1 and 2, wherein {right arrow over (y)} represents said markerprofile, {right arrow over (z)}₁ represents said CP-CML template, and{right arrow over (z)}₂ represents said ADV-CML template, P₁ representssaid correlation coefficient between said marker profile and said CP-CMLtemplate, and P₂ represents said correlation coefficient between saidmarker profile and said ADV-CML template.

In one embodiment, the measurement of each gene product in said CP-CMLtemplate or said ADV-CML template is an average of the measurements ofsaid gene product in a plurality of CP-CML patients or in a plurality ofADV-CML patients, respectively.

In one embodiment, said measurement of each gene product in said markerprofile is a relative level of said gene product in said cell sampletaken from the patient versus level of said gene product in a referencepool, represented as a log ratio; the respective measurement of eachgene product in said CP-CML template is a relative level of said geneproduct representative of level of said gene product in a plurality ofCP-CML patients versus level of said gene product in a reference pool,represented as a log ratio; and the respective measurement of each geneproduct in said ADV-CML template is a relative level of said geneproduct representative of level of said gene product in a plurality ofADV-CML patients versus level of said gene product in a reference pool,represented as a log ratio.

In one embodiment, the respective log ratio for each gene product insaid CP-CML template or said ADV-CML template is an average of the logratios for said gene product in a plurality of CP-CML patients or in aplurality of ADV-CML patients, respectively.

In another preferred embodiment, said progression classifier is anartificial neural network (ANN) or a support vector machine (SVM).

The invention also provides a method for assigning a therapeutic regimenfor a CML patient, comprising (a) determining the progression of saidpatient using any of the above described methods; and (b) assigning saidpatient a therapeutic regimen according to the status of progressiondetermined in step (a). In one embodiment, said patient is determined tobe in ADV-CML, and said therapeutic regimen assigned to said patientcomprises bone marrow transplant.

The invention also provides a method for enrolling CML patients for aclinical trial of an agent for treating CML, comprising (a) determiningthe progression of said patient using any of the above describedmethods; and (b) assigning each patient having a CP-CML to one patientgroup and each patient having an ADV-CML to another patient group, atleast one of said patient group being enrolled in said clinical trial.

The invention also provides a method for determining the responsivenessof a chronic myeloid leukemia (CML) patient to imatinib mesylate (IM),comprising (a) determining the progression of said patient using any ofthe above described methods; and (b) determining said patient asresponsive to IM treatment if said marker profile is classified as aCP-CML profile, or determining said patient as resistant to IM treatmentif said marker profile is classified as an ADV-CML profile.

In another aspect, the invention provides a method for determining theresponsiveness of a chronic myeloid leukemia (CML) patient to imatinibmesylate (IM), comprising (a) classifying a marker profile comprisingmeasurements of a plurality of gene products in a cell sample taken fromsaid patient as an IM-sensitive profile or an IM-resistant profile,wherein said gene products are respectively products of at least 5 ofthe genes listed in Table 4 or respective functional equivalentsthereof; and (b) determining said patient as responsive to IM treatmentif said marker profile is classified as an IM-sensitive profile, ordetermining said patient as resistant to IM treatment if said markerprofile is classified as an IM-resistant profile. In one embodiment,said plurality of gene products are of at least 5 of the genes listed inTable 4. In one embodiment, said cell sample is a bone marrow sample ora peripheral blood sample.

In one embodiment, the method further comprises obtaining said markerprofile by a method comprising measuring said plurality of gene productsin a cell sample taken from said patient.

In preferred embodiments, said gene products are products of at least10, at least 20, at least 40, at least 70, at least 100, or at least 200of the genes, respectively, listed in Table 4.

In one embodiment, each of said gene products is a gene transcript.

In one embodiment, measurement of each said gene transcript is obtainedby a method comprising contacting a positionally-addressable microarraywith nucleic acids from said cell sample or nucleic acids derivedtherefrom under hybridization conditions, and detecting the amount ofhybridization that occurs, said microarray comprising one or morepolynucleotide probes complementary to a hybridizable sequence of eachsaid gene transcript.

In another embodiment, each of said plurality of gene products is aprotein.

In a preferred embodiment, said classifying is carried out by a methodcomprising using a progression classifier, wherein said progressionclassifier receives an input comprising said marker profile and providesan output comprising data indicating whether said marker profile is anIM-sensitive profile or an IM-resistant profile.

In one embodiment, said progression classifier is trained with trainingdata from a plurality of tranining CML patients, wherein said trainingdata comprise for each of said plurality of training CML patients (i) atraining maker profile comprising measurements of said plurality of geneproducts in a cell sample taken from said training patient; and (ii)data indicating whether said training patient is sensitive or resistantto imatinib mesylate.

In one embodiment, said progression classifier comprises an IM-sensitivetemplate comprising measurements of said plurality of gene productsrepresentative of measurements of said plurality of genes products in aplurality of patients responsive to IM treatment and/or an IM-resistanttemplate comprising measurements of said plurality of gene productsrepresentative of measurements of said plurality of genes products in aplurality of patients resistant to IM treatment, and said step ofclassifying is carried out by a method comprising (a1) comparing saidmarker profile with said IM-sensitive template and/or said IM-resistanttemplate; and (a2) classifying said marker profile as a IM-sensitiveprofile if said marker profile has a high similarity to saidIM-sensitive template and/or has a low similarity to said IM-resistanttemplate, or classifying said marker profile as a IM-resistant profileif said marker profile has a high similarity to said IM-resistanttemplate and/or has a low similarity to said IM-sensitive template,wherein a high similarity corresponds to a degree of similarity above apredetermined threshold, and wherein a low similarity corresponds to adegree of similarity no greater than said predetermined threshold.

In a specific embodiment, said step of classifying is carried out by amethod comprising (a1) comparing said marker profile with saidIM-sensitive template or said IM-resistant template; and (a2)classifying said marker profile as an IM-sensitive profile if saidmarker profile has a high similarity to said IM-sensitive template orhas a low similarity to said IM-resistant template, or classifying saidmarker profile as a IM-resistant profile if said marker profile has ahigh similarity to said IM-resistant template or has a low similarity tosaid IM-sensitive template, wherein a high similarity corresponds to adegree of similarity above a predetermined threshold, and wherein a lowsimilarity corresponds to a degree of similarity no greater than saidpredetermined threshold.

In another specific embodiment, said step of classifying is carried outby a method comprising (a1) comparing said marker profile with saidIM-sensitive template and said IM-resistant template; and (a2)classifying said marker profile as an IM-sensitive profile if saidmarker profile has a higher similarity to said IM-sensitive templatethan to said IM-resistant template, or classifying said marker profileas a IM-resistant profile if said marker profile has a higher similarityto said IM-resistant template than to said IM-sensitive template.

In one embodiment, said similarity to said IM-sensitive template isrepresented by a correlation coefficient between said marker profile andsaid IM-sensitive template, and said similarity to said IM-resistanttemplate is represented by a correlation coefficient between said markerprofile and said IM-resistant template.

In one embodiment, said correlation coefficients between said markerprofile and said IM-sensitive template and said IM-sensitive templateare respectively calculated according to the equation

P _(i)=({right arrow over (z)} _(i) ·{right arrow over (y)})/(∥{rightarrow over (z)} _(i) ∥·∥{right arrow over (y)}∥)

where i=1 and 2, wherein {right arrow over (y)} represents said markerprofile, {right arrow over (z)}₁ represents said IM-sensitive template,and {right arrow over (z)}₂ represents said IM-resistant template, P₁represents said correlation coefficient between said marker profile andsaid IM-sensitive template, and P₂ represents said correlationcoefficient between said marker profile and said IM-resistant template.

In one embodiment, the measurement of each gene product in saidIM-sensitive template or said IM-resistant template is an average of themeasurements of said gene product in a plurality of patients responsiveto IM treatment or in a plurality of patients resistant to IM treatment,respectively.

In one embodiment, said measurement of each gene product in said markerprofile is a relative level of said gene product in said cell sampletaken from the patient versus level of said gene product in a referencepool, represented as a log ratio; the respective measurement of eachgene product in said IM-sensitive template is a relative level of saidgene product representative of level of said gene product in a pluralityof patients responsive to IM treatment versus level of said gene productin a reference pool, represented as a log ratio; and the respectivemeasurement of each gene product in said IM-resistant template is arelative level of said gene product representative of level of said geneproduct in a plurality of patients resistant to IM treatment versuslevel of said gene product in a reference pool, represented as a logratio.

In one embodiment, the respective log ratio for each gene product insaid IM-sensitive template or said IM-resistant template is an averageof the log ratios for said gene product in a plurality of patientsresponsive to IM treatment or in a plurality of ADV-CML patients,respectively.

In another preferred embodiment, said progression classifier is anartificial neural network (ANN) or a support vector machine (SVM).

The invention also provides a method for assigning a treatment regimenfor a CML patient, comprising (i) determining whether said patient isresponsive or resistant to imatinib mesylate using a method as describedabove; and (ii) assigning said patient a treatment regimen comprisingbone marrow transplant if said patient is determined to be resistant toimatinib mesylate.

The invention also provides a method for enrolling CML patients for aclinical trial of a treatment modality for treating CML, comprising (i)determining whether said patient is responsive or resistant to imatinibmesylate using a method as described above; and (ii) assigning eachpatient who is predicted to be resistant to imatinib mesylate to onepatient group and each patient who is predicted to be responsive toimatinib mesylate to another patient group, at least one of said patientgroup being enrolled in said clinical trial.

In still another aspect, the invention provides a method for treating apatient having chronic myeloid leukemia (CML), comprising administeringto said patient a treatment regimen, said treatment regimen comprisingone or more agents that modulate the expression and/or activity of oneor more different genes listed in one or more of Tables 2a, 2b, 5a and5b and/or their encoded proteins, wherein said patient exhibits aberrantregulation of said one or more genes.

In one embodiment, said one or more different genes are selected fromthe different genes listed in one or more of Tables 2a and 5a.

In another embodiment, said one or more different genes are selectedfrom the genes listed in both Tables 2a and 5a, i.e., genes common inTables 2a and 5a.

In still another embodiment, said one or more different genes areselected from the genes listed in Table 3.

In one embodiment, said one or more different genes are selected fromthe up-regulated genes listed in Table 3, and said treatment regimencomprises a substance selected from the group consisting of siRNA,antisense nucleic acid, ribozyme, and triple helix forming nucleic acid,each reducing the expression of one or more of said one or moredifferent genes in said patient.

In another embodiment, said one or more different genes are selectedfrom the up-regulated genes listed in Table 3, and said treatmentregimen comprises a substance selected from the group consisting ofantibody, peptide, and small molecule, each reducing the activity of oneor more of proteins encoded by said one or more different genes in saidpatient.

In a preferred embodiment, said treatment regimen comprises an siRNAtargeting said one or more different genes.

In preferred embodiment, said one or more different genes consisting of2, 3, 4, 5, 6, or 10 different genes.

In another embodiment, said one or more different genes are selectedfrom the down-regulated genes listed in Table 3, and said treatmentregimen comprises subjecting said patient to gene therapy, said genetherapy enhancing the expression of said one or more different genes insaid patient.

In one embodiment, the methods of the invention further comprisesdetermining a transcript level of each of said one or more differentgenes, and said patient is determined to exhibit aberrant regulation ofsaid different gene if said transcript level deviated from apredetermined threshold level. In some embodiments, said transcriptlevel deviates from said predetermined threshold level by at least1.5-fold, 2-fold or 3-fold.

In one embodiment, each said transcript level is determined by a methodcomprising measuring the transcript level of said different gene usingone or more polynucleotide probes, each of said one or morepolynucleotide probes comprising a nucleotide sequence complementary toa hybridizable sequence in said transcript of said different gene. Inone embodiment, said one or more polynucleotide probes arepolynucleotide probes on a microarray.

In another embodiment, each said transcript level is determined by amethod comprising measuring the transcript level of said different geneusing quantitative reverse transcriptase PCT (qRT-PCR).

In still another aspect, the invention provides a method for treating apatient having chronic myeloid leukemia (CML), comprising administeringto said patient a treatment regimen, said treatment regimen comprising(i) an effective amount of imatinib mesylate (IM), and (ii) an agentother than IM, wherein said agent modulates the expression and/oractivity of 1, 2, 3, 4, 5, 10 or more of the genes listed in Table 4and/or their encoded proteins, and wherein said patient exhibitsaberrant regulation of said one or more genes.

In one embodiment, said one or more genes are selected from the groupconsisting of the up-regulated genes listed in Table 4, and said agentcomprises a substance selected from the group consisting of siRNA,antisense nucleic acid, ribozyme, and triple helix forming nucleic acid,each reducing the expression of one or more of said one or more genes insaid patient.

In another embodiment, said one or more genes are selected from thegroup consisting of the up-regulated genes listed in Table 4, and saidagent comprises a substance selected from the group consisting ofantibody, peptide, and small molecule, each reducing the activity of oneor more of proteins encoded by said one or more genes in said patient.

In one embodiment, said treatment regimen comprises an siRNA targetingsaid one or more target genes.

In some embodiments, said one or more genes consists of at least 2, 3,4, 5, 6, or target genes.

In one embodiment, said one or more genes are selected from the groupconsisting of the down-regulated genes listed in Table 4, and said agentcomprises subject said patient to gene therapy, said gene therapyenhancing the expression of said one or more genes in said patient.

The methods can further comprises determining a transcript level of eachsaid gene, and said patient is determined to exhibit aberrant regulationof said gene if said transcript level deviated from a predeterminedthreshold level. In some embodiment, said transcript level deviates fromsaid predetermined threshold level by at least 1.5-fold, 2-fold or3-fold.

In one embodiment, each said transcript level is determined by a methodcomprising measuring the transcript level of said gene using one or morepolynucleotide probes, each of said one or more polynucleotide probescomprising a nucleotide sequence complementary to a hybridizablesequence in said transcript of said different gene.

In one embodiment, said one or more polynucleotide probes arepolynucleotide probes on a microarray.

In another embodiment, each said transcript level is determined by amethod comprising measuring the transcript level of said CML target geneusing quantitative reverse transcriptase PCT (qRT-PCR).

In still another aspect, the invention provides a method for diagnosingwhether a patient has advanced phase chronic myeloid leukemia (CML),comprising (a) contacting cells a cell sample from said patient with anantibody conjugate, said antibody conjugate comprising an antibody thatbinds a PRAME protein, said antibody being conjugated with a label; and(b) detecting said label on said cells, wherein detection of said labelabove a predetermined threshold indicates that said patient has advancedphase CML. The cell sample can be a bone marrow sample or a peripheralblood sample.

In one embodiment, said antibody is a monoclonal antibody.

In another embodiment, said label is fluorescence label, and saiddetecting is carried out using a fluorescence activated cell sorter.

In still another aspect, the invention provides a method for treating apatient having chronic myeloid leukemia (CML), comprising administeringto said patient a therapeutically sufficient amount of an antibody,wherein said antibody binds a PRAME protein, and wherein said patientexpresses PRAME protein on hematopoetic stem cells and/or immaturemyeloid cells. The invention also provides a method for treating apatient having chronic myeloid leukemia (CML), comprising administeringto said patient a therapeutically sufficient amount of an antibodyconjugate comprising an antibody that binds a PRAME protein, saidantibody being conjugated with a therapeutic molecule, wherein saidpatient expresses PRAME protein on hematopoetic stem cells and/orimmature myeloid cells.

In one embodiment, said antibody is a monoclonal antibody.

The invention also provides a method for ex vivo depletion of advancedphase hematopoetic stem cells and/or immature myeloid cells from a bonemarrow or peripheral blood sample of a patient, comprising (a)incubating said bone marrow or peripheral blood sample with an antibodythat binds a PRAME protein; and (b) removing cells having said antibodyattached. The invention also provides a method for treating a patienthaving chronic myeloid leukemia (CML), comprising (i) depleting advancedphase hematopoetic stem cells and/or immature myeloid cells from a bonemarrow or peripheral blood sample of said patient using the methoddescribed above; and (ii) transplanting the sample obtained in step (i)to said patient.

In still another aspect, the invention provides a method for identifyinga set of genes that are associated with progression of chronic myeloidleukemia (CML), comprising: (a) subtracting from each of a plurality ofCML expression profiles a CD34+ expression profile to obtain a pluralityof CD34+(−) CML expression profiles, each said CML expression profilecomprising levels of expression of a plurality of genes in cells of oneof a plurality of chronic myeloid leukemia (CML) patients, said CD34+expression profile comprising levels of expression of said plurality ofgenes in non cancerous immature CD34+ cells, said plurality of CMLpatients comprising patients of different phases of CML; (b) comparingsaid plurality of CD34+(−) CML expression profiles; and (c) identifyingone or more genes that exhibit significant differences in levels ofexpression between different phases of CML across said plurality ofCD34+(−) CML expression profiles.

In one embodiment, said comparing is carried out by ANOVA and saididentifying is carried out by identifying one or more genes one or moregenes whose p-value corresponds to a predetermined significance level.In one embodiment, said predetermined significance level is p<10⁻⁸.

The method can further comprise: (d) comparing levels of expression ofsaid identified genes between cells of CML blast crisis and normalimmature CD34+ cells; and (e) selecting those genes that exhibitsignificant differences in expression.

In another embodiment, said comparing is carried out by ANOVA and saidselecting is carried out by selecting one or more genes whose p-valuecorresponds to a predetermined significance level. In one embodiment,said predetermined significance level is p-value <0.01%.

The invention also provides a computer system comprising a processor,and a memory coupled to said processor and encoding one or moreprograms, wherein said one or more programs cause the processor to carryout any one of the methods of the invention.

The invention also provides a computer program product for use inconjunction with a computer having a processor and a memory connected tothe processor, said computer program product comprising a computerreadable storage medium having a computer program mechanism encodedthereon, wherein said computer program mechanism may be loaded into thememory of said computer and cause said computer to carry out any one ofthe methods of the invention.

In still another aspect, the invention provides a microarray comprisingfor each of a plurality of genes, said genes being at least 5 of thegenes selected from the group consisting of the genes as identifiedrespectively by SEQ ID NOS: 1-3968, wherein at least one of said 5 genesis not a gene selected from the group consisting of genes as identifiedrespectively by SEQ ID NOS: 56, 65, 70, 177, 190, 199, 1758, 1773, 1774,1776, 1786, 1815, 1823, 3925, 3933, 3947, 3956, and 3961, one or morepolynucleotide probes complementary and hybridizable to a sequence insaid gene, wherein polynucleotide probes complementary and hybridizableto said genes constitute at least 50%, 70%, 80%, 90% or 98% of theprobes on said microarray.

In one embodiment, said plurality of genes is at least 10, 20, 40, 70,100, or 200 genes.

In another embodiment, said plurality of genes is selected from thegroup consisting of the genes listed in Tables 1a and/or 1b.

In still another embodiment, said plurality of genes is selected fromthe group consisting of the genes listed in Tables 2a and/or 2b.

In still another embodiment, said plurality of genes is at least 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all 20 of the geneslisted in Table 3.

In still another embodiment, said plurality of genes are selected fromthe group consisting of the genes listed in Table 4.

In still another embodiment, said plurality of genes is selected fromthe group consisting of the genes listed in Tables 5a and/or 5b.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Genes associated with CML progression. Samples of CML cases inchronic phase, accelerated by cytogenetic criteria only, acceleratedphase, blast crisis, and blast crisis “in remission” were compared to apool of chronic phase RNA. Approximately 3,000 genes were significantlyassociated with progressive disease at a significance level of p<10⁻¹¹.Each row represents one sample, and each column represents one gene. Adarker color indicates over-expression relative to the control pool, anda lighter color indicates low-expression.

FIG. 2. 2 a: Genes differentially expressed in blast crisis CML comparedto normal CD34+ stem cells. CML blast crisis samples with >70% blastswere compared to normal CD34+ bone marrow stem cells. 2 b: Approximately400 genes were significantly differentially expressed between CML blastsand their immature CD34+ normal counterparts (ANOVA P<0.1%). 2 c: Phasegenes corrected for normal CD34+ gene expression (ANOVA P<1×10⁻⁸). Thegene expression of normal CD34+ cells was subtracted from each diseasesample. The resulting pattern reflects genes associated with progressionindependent of normal blast biology.

FIG. 3. Genes expression signature of genes associated with specificpromoter sequences. Genes with specific promoter sequences were testedfor their differential enrichment across different phases of CML (seeMethods). FIG. 3 a shows genes bearing a MZF promoter; FIG. 3 b showsexpression of genes under putative control of delta EF1.

FIG. 4. Gene expression in Imatinib failure cases. 4 a: All CML casesincluding cases of imatinib failure; gene expression is based on thepreviously obtained ˜3,000 phase reporter set. 4 b: Cases are ranked andsorted by the correlation of summed gene expression, with casesrepresenting the most “cp-like” and most “bc-like” forming theboundaries of gene expression patterns. Cases of imatinib failures areshown. 4 c: Genes differentially expressed in imatinib resistant casesthat are not associated with progression gene set. The boxed areasrepresent genes differentially expressed in the imatinib resistant casescompared to blast crisis cases.

FIG. 5. Comparison of gene expression in accelerated phase versus blastphase CML. The graph shows the scatter plot of log(ratio) of all 25Kgenes in blast crisis and accelerated phase cases. Each blue dotrepresents a gene. Thus, genes in the upper left hand box are up inaccelerated phase, but down in blast crisis. Genes in the upper rightbox are up both in accelerated and blast crisis. The gene expressionlevels are very highly correlated between accelerated and blast crisis(r=0.81).

FIG. 6. Phase reporter genes after removal of normal CD34+ signature.The gene expression signature of normal CD34+ cells was subtracted fromthe data of CML cases. The genes shown are the genes differentiallyexpressed across disease phases after genome wide removal of CD34+signatures (p-value of <10⁻⁴).

FIG. 7. Comparison of gene expression between bone marrow and peripheralblood. In three cases of blast crisis samples were simultaneously drawnfrom marrow and blood. The figures show a high correlation of geneexpression for these three cases.

FIG. 8 illustrates an exemplary embodiment of a computer system forimplementing the methods of this invention.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The invention provides molecular markers, i.e., genes, the expressionlevels of which can be used for evaluating the progression of chronicmyeloid leukemia (CML) from chronic phase to advanced phase. Theidentities of these markers and the measurements of their respectivegene products, e.g., measurements of levels (abundances) of theirencoded mRNAs or proteins, can be used by application of a patternrecognition algorithm to develop a progression classifier thatdiscriminates between different phases of CML based on measurements ofsuch gene products in a sample from a patient. As used herein, the term“gene product” includes mRNA transcribed from the gene and proteinencoded by the gene.

Chronic myelogenous leukemia (CML) is characterized by high peripheralwhite blood cell (WBC) counts with granulocyte predominance andextramedullary hematopoiesis. CML typically evolves through 3 clinicallydistinct stages or phases: chronic phase (CP-CML or CP), acceleratedphase (AP-CML or AP), and blast phase (BP-CML or BP), which is alsocalled acute phase or blast crisis (BC-CML or BC). The chronic phaselasts several years and is characterized by accumulation of myeloidprecursors and mature cells in bone marrow, peripheral blood, andextramedullary sites. During the chronic phase, patients typically havefewer than 10% blasts (or 20% blasts and promyelocytes combined) inblood or bone marrow samples. These patients usually have relativelymild symptoms and usually respond to standard treatments. The chronicphase progresses into the accelerated phase, which lasts about 4 to 6months. During the accelerated phase, patients typically have more than10% blasts (or 20% blasts and promyelocytes combined) but less than 30%blasts and promyelocytes in their bone marrow or blood samples. Thesepatients often have fever, poor appetite, and weight loss. Symptoms andblood counts of an AP-CML patient are not as responsive to treatments asthey are during the chronic phase. The leukemia cells often havedeveloped new chromosomal changes, in addition to the Philadelphiachromosome. The accelerated phase progresses to the blast phase, whichlasts for a few months. During the blast phase, patients typically havemore than 30% blasts and promyelocytes in their bone marrow and/or bloodsamples. The blast cells often spread to tissues and organs beyond thebone marrow. The accelerated phase and the blast phase are often groupedtogether into an advanced phase of CML (ADV-CML or ADV). The molecularmarkers of the invention are particular useful for evaluating theprogression of a CML patient from the chronic phase to the advancedphase.

The invention provides a list of genes that are differentially expressedacross different phases of CML (Tables 1a and 1b, infra). This set ofgenes is called the phase reporter geneset. Measurements of geneproducts of these molecular markers, as well as of their functionalequivalents, can be used for staging a CML patient. A functionalequivalent with respect to a gene, designated as gene A, refers to agene that encodes a protein or mRNA that at least partially overlaps inphysiological function in the cell to that of the protein or mRNAencoded by gene A. In particular, CML staging in a patient is carriedout by a method comprising determining whether the patient is in achronic phase or an advanced phase (accelerated phase or blast phase)based on a profile of measurements (e.g., of the levels) of geneproducts of (i.e., encoded by) at least 5, 10, 20, 30, 40, 50, 60, 70,80, 100, 200, 500 or all of the genes in Tables 1a and/or 1b; or of atleast 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of thegenes in Tables 1a and/or 1b, or functional equivalents of such genes,in an appropriate cell sample from the patient, e.g., a bone marrow orblood sample obtained from the patient, wherein at least 1, 2, 3, 5, or10 genes as appropriate are from Table 1a. Such a profile ofmeasurements is also referred to herein as an “expression profile” or a“marker profile.” In a specific embodiment, the evaluation of CMLprogression in a patient is carried out using measurements (e.g., of thelevels) of gene products of (i.e., encoded by) at least 5, 10, 20, 30,40, 50, 60, 70, 80, 100, 200, 500 or all of the genes in Tables 1a; orof at least 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% ofthe genes in Tables 1a, or functional equivalents of such genes. Inanother specific embodiment, the evaluation of CML progression in apatient is carried out using measurements of gene products of less than30, 40, 50, 70, 100, 200, 300, 400, or 500 total genes, in which all orat least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the genes are fromTables 1a and/or 1b or their functional equivalents, or at least 5, 10,20, 30, 40, 50, 60, 70, 80, or 100 of the genes are from Tables 1aand/or 1b or their functional equivalents. In one embodiment, if thepatient expression profile is classified as a CP-CML profile, thepatient is determined as in chronic phase, whereas if the patientexpression profile is classified as a ADV-CML profile, the patient isdetermined as in an advanced phase (accelerated phase or blast crisis).

The invention also provides a list of genes that are associated with CMLprogression (Tables 2a and 2b, infra). These genes are also termed“progression genes” in the application. This set of genes is called theprogression geneset. Measurements of gene products of these molecularmarkers, as well as of their functional equivalents, can be used forstaging a CML patient. Since these genes are associated with CMLprogression, they are also targets for therapeutic intervention of CML.For example, a CML patient exhibiting aberrant regulation of such genescan be treated by therapies targeting such genes. Thus, measurements ofgene products of these molecular markers, as well as of their functionalequivalents, can also be used for determining an appropriated treatmentregimen for a CML patient.

Different subcombination of CML progression genes can also be used.Thus, in various embodiments, the markers that are the genes listed inTables 2a-2b or 3 are used. Measurements of gene products of thesemolecular markers and/or their functional equivalents can be used forevaluating the progression of CML in a patient. The evaluation of CMLprogression in a patient is carried out by a method comprisingdetermining whether the patient is in a chronic phase or an advancedphase (accelerated phase or blast phase) based on a profile ofmeasurements (e.g., of the levels) of gene products of (i.e., encodedby) at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 100, 200 or all of thegenes in Tables 2a and/or 2b, or at least 5, 10, 15 or all of the genesin Table 3; or of at least 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, or 90% of the genes in Tables 2a and/or 2b or in Table 3, orfunctional equivalents of such genes, in an appropriate cell sample fromthe patient, e.g., a bone marrow or peripheral blood sample obtainedfrom the patient, wherein at least 1, 2, 3, 5, or 10 genes asappropriate are from Table 2a. In a specific embodiment, the evaluationof CML progression in a patient is carried out using measurements (e.g.,of the levels) of gene products of (i.e., encoded by) at least 5, 10,20, 30, 40, 50, 60, 70, 80, 100, 200, 300 or all of the genes in Tables2a; or of at least 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or90% of the genes in Tables 2a, or functional equivalents of such genes.In one embodiment, if the patient expression profile is classified as aCP-CML profile, the patient is determined as in chronic phase, whereasif the patient expression profile is classified as a ADV-CML profile,the patient is determined as in an advanced phase (accelerated phase orblast crisis).

The invention also provides a list of genes that are associated withresistance to imatinib mesylate (Table 4, infra). These genes are alsotermed “imatinib resistance genes” in the application. This set of genesis called the imatinib resistance geneset. Measurements of gene productsof these molecular markers, as well as of their functional equivalents,can be used for evaluating the responsiveness of a CML patient toimatinib treatment. The evaluation of responsiveness of a patient toimatinib is carried out by a method comprising determining whether thepatient is likely to be responsive to imatinib treatment based on aprofile of measurements (e.g., of the levels) of gene products of (i.e.,encoded by) at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 100, 200 or allof the genes in Table 4; or of at least 2%, 5%, 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, or 90% of the genes in Table 4, or functional equivalentsof such genes, in an appropriate cell sample from the patient, e.g., abone marrow or peripheral blood sample obtained from the patient. In oneembodiment, if the patient expression profile is classified as aIM-resistance profile, the patient is determined as likely to beresistant to imatinib treatment, whereas if the patient expressionprofile is classified as a IM-sensitive profile, the patient isdetermined as likely to be responsive to imatinib treatment. In aspecific embodiment, a CML patient in the chronic phase is evaluated forresponsiveness to imatinib treatment based on an expression profile ofsuch imatinib resistance genes. If the patient's expression profileindicates that the patient is likely to be resistant to imatinibtreatment, bone marrow transplantation and/or other investigativetreatment regimens may be assigned to the patient.

In another embodiment, the responsiveness of a CML patient to imatinibtreatment can also be evaluated based on expression of phase reportersor progression genes. In this embodiment, the patient expression profilecomprising measurements of phase reporter genes (Table 1a and/or 1b) orprogression genes (Table 2a and/or 2b) is evaluated using a methoddescribed above. If the patient expression profile is classified as aADV-CML profile, the patient is determined as likely to be resistant toimatinib treatment.

The measurements in the profiles of the gene products that are used canbe any suitable measured values representative of the expression levelsof the respective genes. The measurement of the expression level of agene can be direct or indirect, e.g., directly of abundance levels ofRNAs or proteins or indirectly, by measuring abundance levels of cDNAs,amplified RNAs or DNAs, proteins, or activity levels of RNAs orproteins, or other molecules (e.g., a metabolite) that are indicative ofthe foregoing. In one embodiment, the profile comprises measurements ofabundances of the transcripts of the marker genes. The measurement ofabundance can be a measurement of the absolute abundance of a geneproduct. The measurement of abundance can also be a value representativeof the absolute abundance, e.g., a normalized abundance value (e.g., anabundance normalized against the abundance of a reference gene product)or an averaged abundance value (e.g., average of abundances obtained atdifferent time points or from different tumor cell samples from thepatients, or average of abundances obtained using different probes,etc.), or a combination of both. As an example, the measurement ofabundance of a gene transcript can be a value obtained using anAffymetrix® GeneChip® to measure hybridization to the transcript.

In another embodiment, the expression profile is a differentialexpression profile comprising differential measurements of a pluralityof transcripts in a sample derived from the patient versus measurementsof the plurality of transcripts in a reference sample, e.g., a cellsample of normal cells. Each differential measurement in the profile canbe but is not limited to an arithmetic difference, a ratio, or alog(ratio). As an example, the measurement of abundance of a genetranscript can be a value for the transcript obtained using an ink-jetarray or a cDNA array in a two-color measurement. In a preferredembodiment, the reference sample comprise target polynucleotidemolecules from normal cell samples (i.e., cell sample, e.g., bone marrowor peripheral blood, from those not afflicted with CML). In anotherpreferred embodiment, the reference sample comprise targetpolynucleotide molecules from cell samples, e.g., bone marrow orperipheral blood, from chronic phase CML patients.

The invention also provides methods and computer systems for evaluatingthe progression of CML in a patient based on a measured marker profilecomprising measurements of the markers of the present invention, e.g.,an expression profile comprising measurements of transcripts of at leastsome of the genes listed in Tables 1a and/or 1b, e.g., at least 5, 10,20, 30, 40, 50, 60, 70, 80, or 100 in Tables 1a and/or 1b or functionalequivalents of such genes, wherein at least 1, 2, 3, 5 or 10 genes arefrom Table 1a. The methods and systems of the invention use aprogression classifier for evaluating the progression of CML. Theprogression classifier can be based on any appropriate patternrecognition method (such as those described in Section 5.2) thatreceives an input comprising a marker profile and provides an outputcomprising data indicating which phase the patient belongs, i.e.,chronic phase or advanced phase. The progression classifier can beconstructed with training data from a plurality of CML patients for whommarker profiles and progression status are known. The plurality ofpatients used for training the progression classifier is also referredto herein as the training population. The training data comprise foreach patient in the training population (a) a marker profile comprisingmeasurements of gene products of a plurality of genes, respectively, inan appropriate cell sample, e.g., a bone marrow or peripheral bloodsample, taken from the patient; and (b) progression status information(e.g., the CML phase of the patient). Various progression classifiersthat can be used in conjunction with the present invention are describedin Section 5.2., infra. In some embodiments, additional patients havingknown marker profiles and progression status can be used to test theaccuracy of the progression classifier obtained using the trainingpopulation. Such additional patients are also called “the testingpopulation.”

The markers in the marker sets are selected based on their ability todiscriminate patients having different CML phases in a plurality of CMLpatients for whom the progression status are known. Various methods canbe used to evaluate the correlation between marker levels and CMLprogression. For example, genes whose expression levels aresignificantly different across patients in different CML phases can beidentified using an appropriate statistical method, e.g., ANOVA.

The invention also provides methods and compositions for treating apatient having CML by modulating, e.g., enhancing or reducing, theexpression and/or activities of one or more CML progression genes and/ortarget genes and/or their gene products. The invention also providesmethods and compositions for treating a patient having CML bymodulating, e.g., enhancing or reducing, certain CML pathways thatinvolve in CML progression and response. The CML progression genesinclude those genes listed in Tables 2a and 2b. The CML target genesinclude those genes listed in Tables 5a and 5b. The CML pathways includeFLT3; Rras2; beta-catenin; and SOCS2. The invention also providesmethods and compositions for treating a patient having CML bymodulating, e.g., enhancing or reducing, certain proteosomes andchaperone proteins. The invention also provides methods and compositionsfor treating a patient having CML by modulating genes controlled by apromoter selected from the group consisting of the following MZF, deltaEF1, SPI-B, Yin Yang, and Ahr-ARNT. The invention also provides methodsand compositions for treating a patient having CML by modulating, e.g.,reducing, the expression and/or activity of CD47. The invention alsoprovides methods and compositions for treating a patient having CML bytargeting PRAME. The invention is based, at least in part, on theidentification of aberrant regulation of these genes and pathways inCML.

Thus, the invention provides methods and compositions for treating CMLby modulating the expression and/or activity of CML progression genesand/or CML target genes and/or their gene products, and/or by modulatinginteractions of the CML progression genes and/or target genes and/ortheir gene products with other proteins or molecules, e.g., substrates.The methods and compositions can be used for treating CML patient whoexhibit aberrant regulation in such CML progression/target genes. Thus,such methods and compositions can be used in conjunction with imatinibmesylate. In one embodiment, the expression of one or more of the CMLprogression/target genes is modulated, e.g., reduced or enhanced, totreat a CML patient exhibiting aberrant regulation of these CMLprogression/target genes. Such modulation can be achieved by, e.g.,using siRNA, antisense nucleic acid, ribozyme, and/or triple helixforming nucleic acid that target the CML progression/target genes. Inanother embodiment, the activity of one or more CML progression/targetproteins is modulated, e.g., reduced or enhanced, to enhance the effectsof chemotherapy agents. Such modulation can be achieved by, e.g., usingantibodies, peptide molecules, and/or small molecules that target a CMLprogression/target protein.

The invention also provides methods and compositions for treating CML bymodulating the expression and/or activity of imatinib mesylateresistance genes and/or their gene products, and/or by modulatinginteractions of the IM-resistance genes and/or their gene products withother proteins or molecules, e.g., substrates, in combination ofimatinib mesylate. In one embodiment, the expression of one or more ofthe IM-resistance genes is modulated, e.g., reduced or enhanced, totreat a CML patient undergoing imatinib mesylate treatment. Suchmodulation can be achieved by, e.g., using siRNA, antisense nucleicacid, ribozyme, and/or triple helix forming nucleic acid that target theimatinib mesylate genes. In another embodiment, the activity of one ormore imatinib mesylate proteins is modulated, e.g., reduced or enhanced,to enhance the effects of chemotherapy agents. Such modulation can beachieved by, e.g., using antibodies, peptide molecules, and/or smallmolecules that target imatinib mesylate proteins.

The invention also provides methods and compositions for utilizing CMLprogression/target genes or IM-resistance genes, and/or their productsfor screening for agents that modulate their expression and/or activityand/or modulating their interactions with other proteins or molecules.Agents that modulate expression and/or activity of CMLprogression/target genes can be used for treating CML patient exhibitingaberrant regulation of one or more CML progression/target genes. Agentsthat modulate expression and/or activity of IM-resistance genes can beused in combination with IM for treating CML patient exhibitingresistance to IM treatment. Thus, the invention provides methods andcompositions for utilizing CML progression/target genes and geneproducts for screening for agents that are useful in modulatingexpression and/or activity of CML progression/target genes or IMresistance genes and/or their products and/or modulating theirinteractions with other proteins or molecules in a CML patientexhibiting aberrant regulation of one or more CML progression/targetgenes or IM resistance genes. The compositions of the invention includebut not limited to siRNA, antisense nucleic acid, ribozyme, triple helixforming nucleic acid, antibody, peptide or polypeptide molecules, andsmall organic or inorganic molecules.

The present invention also provides methods and compositions foridentifying other extra- or intra-cellular molecules, e.g., genes andproteins, which interacts with the CML progression/target genes or IMresistance genes, and/or their gene products, and/or CML progressionpathways. The present invention also provides methods and compositionsfor treating CML by modulating such cellular constituents and/orpathways.

As used herein, a patient is an animal having CML. The patient can bebut is not limited to a human, or, in a veterinary context, fromnon-human animals such as ruminants, horses, swine or sheep, or fromdomestic companion animals such as felines and canines. In a preferredembodiment, the patient is a human patient. Suitable samples that can beused in conjunction with the present invention include but are notlimited to bone marrow samples and peripheral blood samples.

5.1. Genes Associated with CML Progression and Response

The invention provides molecular marker sets (of genes) that can be usedfor evaluating progression and/or imatinib resistance in a CML patientbased on a profile of the markers in the marker set (containingmeasurements of marker gene products).

Tables 1a and 1b list genes that are differentially expressed acrossdifferent phases of CML. This set of genes is called the phase reportergeneset. The phase reporter genes are identified by their SEQ ID NOs inTables 1a and 1b. Tables 1a and 1b also listed for each gene the logratio of expression level of the gene in samples from patients of aparticular phase (e.g., CP, AP, or BC) versus expression level of thegene in a pool of CML bone marrow samples from chronic phase patients.Each log ratio column thus contains expression levels of markers for aparticular phase. Information for these genes is presented in Table 8.In Table 8, the following information is presented for each gene: geneidentifier (column 1), gene name (column 2), the SEQ ID NO of thesequence of the gene (column 3), and the SEQ ID NO of the probe sequenceused in the present application (column 4). The first column of Table 8shows the identifiers of genes disclosed in the application. The term“SUBS” is shorthand for substance identifier. For those genes listed inTable 8 that have a GenBank® accession number, the GenBank® accessionnumber is listed. For those genes in Table 8 that do not have a GenBank®Accession No, the Contig ID numbers of the transcript sequences in thePhil Green assembly (Nat Genet. 2000 June; 25(2):232-4) is listed. PhilGreen's group at the University of Washington assembled ESTs from theWashington University-Merck Human EST Project and CGAP archives.Analysis of expressed sequence tags indicates 35,000 human genes (NatGenet. 2000 June; 25(2):232-4). This assembly, dated Mar. 17, 2000,resulted in 62,064 contigs representing 795,000 ESTs. These contigs havethe word “contig” included in their identifiers. Table 1a lists phasereporters that were not disclosed in U.S. Patent Application Publication2003/01044026 A1, dated Jun. 5, 2003. Table 1b lists phase reportersthat were also identified in U.S. Patent Application Publication2003/01044026 A1, dated Jun. 5, 2003.

TABLE 1a phase reporter genes SEQ ID NO log(ratio) CP log(ratio) APlog(ratio) BC 1 −0.00406 0.196563 0.331631 2 −0.013036 0.331191 0.136193 −0.01517 −0.1969 −0.51997 4 −0.01226 0.234703 0.506317 5 −0.01055−0.11513 −0.25239 6 0.02333 0.2234 0.385294 7 0.001109 −0.04225 −0.389228 0.022178 0.320491 0.362686 9 −0.01332 −0.22505 −0.26552 10 0.0024910.107514 0.40248 11 −0.03342 −0.12983 −0.34856 12 −0.02396 −0.1739−0.56037 13 0.004316 −0.16534 −0.15954 14 −0.00225 0.464357 0.637155 15−0.06413 −0.10146 −0.58794 16 0.009128 0.235874 0.469511 17 0.0202361.123603 0.742981 18 0.016214 0.159637 0.392829 19 −0.04723 −0.47509−1.36264 21 −0.01095 0.232221 0.294685 22 0.012172 0.427707 0.729027 23−0.01999 −0.21291 −0.36149 24 −0.00972 −0.14706 −0.4052 25 0.004981−0.21328 −0.37135 26 −0.02611 −0.30231 −0.45226 27 0.010514 0.3388240.434019 29 −0.02088 −0.283 −0.45987 30 −0.00198 −0.11265 −0.28724 310.023577 0.770737 0.690215 32 0.008671 −0.0801 −0.28421 33 0.012103−0.15124 −0.15019 34 0.010651 −0.14341 −0.515 35 −0.00126 0.0104890.264385 36 0.027348 0.34774 0.624742 37 0.033762 0.213053 0.520588 380.003765 −0.14306 −0.39624 39 0.033025 0.281292 0.406565 40 −0.06315−0.28017 −1.14257 41 0.007748 0.09581 0.335903 42 −0.01732 −0.09377−0.68791 43 0.018086 −0.22492 −0.285 44 0.014232 −0.27373 −0.31289 450.036197 0.142295 0.466937 46 −0.01022 0.299737 0.425197 47 0.0068220.199214 0.443601 48 0.021602 0.186392 0.33675 49 −0.03649 −0.26722−0.49009 52 0.008248 0.502971 0.507442 53 0.040187 0.687502 0.564688 54−0.00051 −0.10576 −0.40709 55 −0.01352 −0.22612 −0.49128 57 −0.052650.433648 0.40219 58 0.019239 0.187127 0.325353 59 0.006451 −0.22186−0.18506 60 0.010201 0.615117 1.017473 61 0.013254 −0.23449 −0.26153 620.012036 −0.20146 −0.36216 63 0.018656 0.262829 0.530868 64 −0.01623−0.1428 −0.50841 66 −0.00346 −0.1026 −0.30257 67 0.009841 0.3352990.527591 68 0.009665 0.97143 0.990692 69 −0.03517 0.36588 0.442864 710.005961 −0.17466 −0.20803 73 −0.00646 −0.25708 −0.21749 74 −0.0186210.110352 −0.541362 75 −0.00408 −0.21342 −0.26897 76 0.009207 0.7694530.850508 78 0.0123 0.167805 0.337085 79 0.00674 −0.17218 −0.25414 80−0.00232 −0.13768 −0.25962 81 −0.04268 −0.09565 −0.76123 82 −0.00889−0.18131 −0.3448 83 0.00964 0.139417 0.328274 84 −0.03477 0.147022−0.67052 85 −0.0546 −0.22956 −1.32988 86 −0.01987 −0.41057 −0.63814 87−0.00053 −0.16512 −0.19246 89 0.029134 0.166704 0.399066 90 −0.00832−0.13645 −0.3186 92 0.037155 0.284153 0.64532 94 −0.01142 −0.13881−0.3608 95 0.01125 0.10955 0.227757 96 0.012527 0.229295 0.293851 980.060257 0.952532 0.999368 100 −0.0643 −0.33585 −0.59098 101 0.0093630.184372 0.293381 102 −0.0128 −0.2329 −0.54422 103 0.019799 0.4728630.54563 104 0.039449 0.415733 0.576671 106 0.010496 −0.12076 −0.18666107 0.011423 −0.16555 −0.23653 108 −0.08443 1.178885 0.802082 1090.013994 0.264328 0.401994 110 0.04438 0.40653 0.580366 111 0.0271080.265955 0.604212 112 0.003332 −0.25986 −0.29846 113 −0.01029 −0.26712−0.2846 114 −0.05586 −0.21334 −0.82293 115 0.009594 0.017981 0.208686117 −0.01023 0.452998 0.673941 118 −0.00659 0.490457 0.517515 119−0.02254 0.744289 0.818592 120 −0.01441 −0.29009 −0.5309 121 −0.01153−0.19616 −0.33788 122 0.028602 0.405315 0.525104 123 −0.00564 0.3557020.57473 124 0.005664 0.194653 0.230888 125 0.029794 0.454278 0.726423126 −0.01071 −0.33686 −0.43968 127 0.037702 0.541984 0.729726 128−0.00753 0.139932 0.246875 129 0.024429 1.375049 1.029358 130 −0.01338−0.13678 −0.28729 131 0.014108 0.432232 0.771513 132 0.026976 0.4255440.61667 133 0.024633 0.146129 0.39073 135 −0.00713 −0.09868 −0.64744 136−0.03239 −0.08145 −0.37526 137 −0.04003 −0.24301 −0.62499 138 −0.003080.502829 0.723824 139 0.006495 0.731382 0.863995 140 0.001806 −0.20936−0.37679 141 −0.03144 −0.20901 −0.55634 143 0.007968 −0.15803 −0.23468144 −0.03705 −0.14512 −0.62385 145 0.027758 0.144793 0.533543 146−0.01241 −0.08289 −0.71342 147 0.024977 −0.11774 −0.37273 148 −0.03021−0.24989 −0.41756 149 −0.07893 −0.2035 −1.0393 151 0.000992 0.4893960.562018 152 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0.4141 3558 0.032499 0.074678 0.253153 3559 0.008088 0.3018920.453923 3560 0.004516 0.219196 0.385653 3561 −0.00872 −0.14402 −0.30153562 0.011229 0.19481 0.270765 3563 0.002252 0.197059 0.467898 35640.004196 −0.17839 −0.35812 3565 0.005919 0.433496 0.704711 3566 0.0141410.259842 0.625664 3567 0.002687 −0.07275 −0.16865 3568 0.019386 0.1807560.320826 3569 0.008055 0.236448 0.463364 3570 −0.00885 −0.19005 −0.189433571 −0.01066 −0.2524 −0.31281 3572 0.003586 0.175294 0.33668 35730.003077 −0.16699 −0.2679 3574 0.010204 −0.24174 −0.21023 3575 −0.01722−0.23788 −0.5273 3576 −0.00986 −0.15833 −0.35006 3577 0.002417 0.1159330.275389 3578 0.01931 0.128265 0.257442 3579 −0.00892 −0.21633 −0.263413580 −0.00471 −0.23215 −0.4848 3581 0.020012 −0.19936 −0.17456 3582−0.03815 −0.31028 −0.83405 3583 0.050287 −0.01954 0.220994 3584 −0.00585−0.12787 −0.3086 3585 −0.00877 0.285035 0.313925 3586 0.023951 0.4619680.522236 3587 −0.03648 −0.06649 −0.96644 3588 −0.0798 −0.35864 −0.614443589 −0.01895 −0.18531 −0.59784 3590 −0.00434 −0.0927 −0.57452 3591−0.01872 −0.15803 −0.39983 3592 0.034991 0.443566 0.697839 3593 0.003399−0.19622 −0.33779 3594 −0.00647 −0.26511 −0.28231 3595 0.02467 0.2067960.445373 3596 −0.05031 −0.1575 −0.48587 3597 0.01621 −0.09026 −0.158023598 0.012908 −0.04883 −0.1707 3599 −0.00487 −0.18513 −0.31987 3600−0.00359 −0.15119 −0.29052 3601 −0.0151 −0.13785 −0.44486 3602 −0.0169−0.22645 −0.42297 3603 0.005186 −0.17402 −0.16865 3604 −0.05188 0.3155350.632687 3605 0.023942 0.83018 0.88166 3606 0.025262 0.245762 0.3423643607 0.011981 −0.24067 −0.45907 3608 0.00673 0.18853 0.415095 3609−0.01799 −0.22257 −0.34049 3610 −0.01097 −0.04613 −0.41743 3612 −0.01484−0.1804 −0.4596 3613 0.000939 0.263793 0.678549 3614 0.006779 −0.2545−0.29857 3615 0.015733 0.199486 0.348857 3616 0.027123 0.254658 0.407393617 −0.02985 −0.1815 −0.3909 3618 −0.05222 −0.31387 −0.6686 36190.012011 0.093853 0.436918 3621 −0.03416 −0.08213 −0.76259 3622 0.012578−0.13075 −0.23829 3623 −0.000007 0.238639 0.514736 3624 −0.01407−0.01854 −0.6361 3625 0.03931 0.356907 0.463023 3626 0.018908 0.1553170.368218 3627 −0.018961 −0.122255 −0.455286 3628 0.014716 0.2067840.434224 3629 −0.07553 −0.33141 −0.9787 3630 0.015157 0.273984 0.2471173631 −0.00033 0.200936 0.41693 3633 0.007665 0.242867 0.368278 36340.009517 0.749121 0.730716 3635 −0.00042 −0.03395 −0.27982 3636 0.0148690.177299 0.385549 3637 −0.00089 0.343397 0.523406 3638 −0.01318 −0.24177−0.26026 3639 0.015299 0.166454 0.312326 3641 −0.02405 −0.22617 −0.364823643 −0.01067 −0.22275 −0.30837 3644 0.015624 0.272495 0.42811 36450.02679 0.139602 0.304642 3647 0.016106 −0.23904 −0.34971 3648 −0.007850.415134 0.576215 3649 −0.03814 −0.24153 −0.62728 3651 −0.00168 0.1789460.296663 3652 0.005417 0.201231 0.293373 3653 0.020992 0.098499 0.3235633654 0.009897 0.171846 0.304385 3655 −0.009543 −0.030372 0.280245 36560.005039 0.109044 0.437077 3657 0.009618 −0.13852 −0.34652 3658 0.010488−0.100563 −0.316822 3659 0.022109 0.00349 0.254205 3660 −0.029240.248024 0.349343 3661 −0.01618 −0.25316 −0.5936 3662 −0.00179 −0.29298−0.4016 3663 0.010692 0.195257 0.259274 3664 −0.02055 −0.16417 −0.638813665 0.006512 −0.20855 −0.22497 3666 0.014762 0.130635 0.27316 36670.005038 −0.15002 −0.3011 3668 −0.0037 0.161125 0.440317 3669 −0.014880.17173 0.377036 3670 0.004662 0.204447 0.405003 3671 0.031363 0.2250540.391684 3672 −0.01716 0.363938 0.454998 3673 −0.02599 −0.26151 −0.858523674 0.007781 0.240323 0.617296 3675 0.017188 0.381003 0.584545 3676−0.01941 −0.18262 −0.52435 3678 −0.07755 −0.25462 −1.21457 3679 0.0295030.26528 0.545758 3680 −0.01146 −0.05606 −0.57839 3681 0.02916 0.2847170.399181 3682 0.031311 0.886442 1.043437 3684 −0.05039 −0.22784 −0.675363687 0.025134 0.077778 0.233685 3688 −0.03452 −0.2365 −0.6591 36890.020959 0.135435 0.442065 3690 −0.00061 −0.22418 −0.21696 3691 0.0306150.368867 0.463789 3693 0.008242 0.13538 0.238988 3694 0.022164 0.244850.369787 3695 0.008348 0.345415 0.445491 3697 0.027044 0.275282 0.4230663698 0.008222 0.350065 0.740909 3699 −0.00952 −0.19156 −0.22617 3700−0.00774 −0.16099 −0.19923 3701 −0.05313 −0.33669 −0.5235 3702 0.0038560.209935 0.358961 3703 0.007194 −0.37491 −0.31409 3704 0.001122 0.27610.371209 3705 −0.00709 0.357332 0.489837 3706 0.040931 0.462946 0.600493707 −0.00516 0.271088 0.294429 3708 0.00797 0.305948 0.372261 3709−0.01333 −0.34526 −0.32565 3710 −0.00842 0.743893 0.603555 3712 0.005041−0.17492 −0.29702 3713 −0.0289 −0.19531 −0.40228 3714 0.011165 0.1550110.279136 3715 −0.00133 0.390666 0.773649 3716 0.021292 0.217723 0.5320743717 0.029764 0.133139 0.363509 3719 −0.00569 0.272222 0.395599 37200.006975 0.316981 −0.554667 3721 −0.00718 0.174198 0.213069 3722−0.01824 −0.14028 −0.55819 3723 0.001449 0.433877 0.750806 3724 −0.06438−0.34026 −0.90631 3726 0.016783 0.074532 0.32937 3727 −0.023638−0.142935 −0.651747 3728 0.005353 0.185561 0.374248 3729 0.0153330.466716 0.338765 3730 −0.11273 −0.34033 −0.74304 3731 −0.052 −0.44987−1.00602 3732 0.001521 0.087123 0.219262 3733 −0.00774 0.297037 0.4117443734 0.007834 −0.27308 −0.2795 3735 −0.0003 0.1427 0.284445 3736−0.00304 0.247981 0.419058 3737 −0.05269 −0.14303 −0.9691 3738 0.0587990.23747 0.50269 3739 −0.02901 −0.34538 −0.60565 3740 0.008498 0.1004320.280781 3741 −0.0008 0.258263 0.455968 3742 −0.04584 0.066503 0.3752833743 −0.03349 0.288905 0.502598 3744 −0.04514 −0.31129 −1.31612 37450.008607 0.236502 0.379077 3747 0.025051 0.654614 0.673397 3748 −0.00402−0.23433 −0.60235 3749 −0.03559 1.065448 1.023898 3750 −0.02419 0.2137750.639856 3751 −0.03336 −0.27007 −0.76418 3752 −0.0443 0.339835 0.4988223753 −0.01658 0.10543 0.226121 3754 0.009493 0.275559 0.623179 3755−0.021919 0.195442 0.379175 3756 0.007138 0.218329 0.357365 3757−0.00525 −0.21511 −0.32728 3758 0.012473 0.201175 0.362596 3759 −0.01279−0.2507 −0.53842 3760 0.025025 0.151079 0.286126 3761 0.013849 0.1499880.305557 3762 −0.02366 −0.28636 −0.81937 3764 −0.01564 −0.19303 −0.260923766 −0.0078 0.33788 0.559023 3767 −0.14766 −0.58681 −0.8303 3768−0.02365 −0.02657 −0.40423 3769 −0.07505 −0.45329 −0.81364 3770 0.0142560.252952 0.791686 3771 0.000762 0.414331 0.473745 3772 −0.04075 −0.10969−0.87339 3773 0.009132 −0.19384 −0.26354 3774 0.006782 0.308886 0.5867223775 0.016697 −0.13758 −0.22465 3776 −0.00641 −0.09848 −0.32179 3777−0.01008 −0.30175 −0.74848 3778 −0.18892 −0.16936 −0.96093 3779 0.0151980.460693 0.920111 3780 −0.00343 0.30979 0.443498 3781 0.007713 −0.22269−0.19107 3782 −0.00516 −0.21752 −0.43031 3783 0.008031 −0.275 −0.269593784 0.001544 0.152755 0.22911 3786 0.033983 0.314454 0.467167 3787−0.00797 −0.17558 −0.34756 3788 −0.01013 0.252803 0.451763 3789 0.011368−0.17659 −0.27607 3790 −0.01187 0.559225 0.865392 3791 0.007796 −0.11536−0.75804 3794 −0.02133 −0.24973 −0.60104 3795 0.006022 −0.33209 −0.268623796 0.010623 0.370266 0.38694 3797 0.014382 −0.13074 −0.1862 3798−0.00565 −0.31968 −0.72164 3799 −0.00825 −0.25969 −0.45754 3801 −0.00696−0.08637 −0.25043 3802 0.017105 0.245965 0.524084 3803 0.012106 −0.10429−0.39847 3805 0.000356 0.413256 0.478106 3806 0.010934 0.29635 0.3862023807 0.000112 −0.09254 −0.20172 3808 −0.029 −0.27661 −0.49614 38090.010957 0.143925 0.427276 3810 0.013606 0.288317 0.384979 3811 0.00107−0.14349 −0.23862 3813 0.015757 0.049963 0.322916 3814 0.012775 0.2687040.489882 3815 −0.00178 −0.24858 −0.55539 3816 0.020478 0.328518 0.3634963817 0.024418 0.191881 0.339502 3818 −0.01942 −0.29161 −0.28157 38190.000103 0.270294 0.325421 3820 −0.01143 0.488676 1.0676 3821 −0.009520.403054 0.422651 3822 0.009236 −0.18298 −0.28602 3823 −0.00386 −0.02828−0.23222 3824 0.014109 0.222256 0.352421 3825 0.02032 0.265215 0.4591233826 0.033585 0.252623 0.438713 3827 −0.03236 −0.26125 −0.51846 38280.034594 0.156209 0.285878 3829 0.020227 0.248677 0.346795 3830 0.0149780.091181 0.209185 3831 −0.00336 −0.26565 −0.32013 3832 −0.01958 −0.3121−0.42927 3833 0.026113 0.382008 0.532301 3834 0.023708 −0.1401 −0.303313835 0.005344 0.232229 0.33731 3837 0.015978 0.148698 0.33504 3838−0.06039 −0.39414 −1.08079 3839 −0.05249 −0.43012 −0.97039 3840 0.0353520.420428 0.634365 3841 0.014726 0.065969 0.296027 3842 0.014931 0.3377950.48071 3843 0.000632 0.084208 0.363903 3846 −0.12428 −0.61888 −1.148683847 0.024094 0.242898 0.532951 3848 0.014222 −0.20545 −0.18744 3850−0.0071 −0.39614 −1.31291 3851 0.012684 0.070752 0.274745 3852 0.023720.172396 0.342361 3853 0.00189 −0.145487 −0.229147 3854 −0.00101−0.21912 −0.72961 3855 0.007222 −0.15336 −0.26965 3856 0.007543 −0.15408−0.15187 3858 0.018762 −0.28212 −0.40115 3859 −0.08983 −0.08099 −0.961913860 0.004134 0.11989 0.775235 3861 −0.00476 0.799769 0.775464 3862−0.02069 0.619347 0.552404 3863 0.023825 0.198966 0.288914 3864 0.002065−0.18112 −0.3627 3865 0.023799 0.373823 0.502792 3866 −0.07514 −0.16355−1.15587 3867 −0.02357 0.426881 0.768005 3868 −0.06742 −0.22372 −1.483623869 0.007952 −0.20656 −0.18147 3870 −0.00995 −0.18825 −0.32561 3871−0.09391 −0.49811 −0.67155 3872 −0.01577 −0.30748 −0.36469 3873 0.00135−0.177 −0.26574 3874 0.01437 −0.27493 −0.64992 3875 0.008601 0.1754170.368725 3877 0.0215 0.239552 0.543968 3878 0.007867 −0.14612 −0.2193879 −0.02127 −0.13431 −0.5214 3881 −0.01449 −0.22729 −0.38659 3882−0.008 −0.28045 −0.35033 3883 −0.00282 −0.22456 −0.3246 3884 −0.010060.125335 0.437432 3885 −0.0341 −0.33793 −0.64981 3886 −0.02831 −0.22518−0.44843 3887 −0.00342 −0.15249 −0.46289 3888 0.014393 0.484554 0.4959313889 0.001776 0.262078 0.383028 3890 0.011023 −0.01062 −0.44164 38920.004332 −0.00059 −0.38242 3893 0.001464 −0.14286 −0.18126 3894 −0.01231−0.2316 −0.32005 3895 0.018186 0.089257 0.210466 3896 0.0075 −0.17357−0.27499 3897 −0.00568 −0.14148 −0.37829 3898 0.002511 −0.14907 −0.152973899 −0.0092 −0.1654 −0.41466 3900 0.01744 0.108167 0.303529 3902−0.21525 −0.62727 −0.88264 3903 0.012294 0.101754 0.422339 3904 0.007328−0.12993 −0.17647 3906 0.032547 0.2237 0.374842 3907 0.020824 0.4552490.666732 3908 0.001958 −0.08941 −0.20901 3909 −0.03403 −0.28041 −0.667613910 0.005124 0.373303 0.456396 3911 0.007527 0.436713 0.635286 3912−0.01004 −0.18805 −0.1945 3913 −0.13841 0.130768 −0.78612 3914 0.005593−0.24982 −0.45921 3916 0.007871 0.294561 0.472056 3917 0.000456 0.3504530.512085 3918 −0.00721 −0.20685 −0.30782 3919 0.00249 0.4553 0.4674183920 0.003433 0.234106 0.347743 3921 0.02159 0.267666 0.272491 3922−0.01034 −0.23596 −0.40316 3923 −0.0218 −0.17331 −0.31503 3924 −0.01052−0.2608 −0.45258 3926 0.005481 −0.19415 −0.38862 3927 −0.00198 −0.15223−0.26378 3928 −0.00481 −0.19212 −0.60011 3929 −0.02907 −0.31237 −0.671153930 0.018932 0.502499 0.630779 3931 0.007823 0.330178 0.374828 3932−0.00625 −0.19177 −0.36188 3934 −0.01138 −0.16719 −0.62327 3936 0.013418−0.12059 −0.21994 3937 −0.00602 −0.17249 −0.19886 3938 −0.00093 −0.18338−0.21621 3940 −0.0063 0.32237 0.447277 3941 −0.03123 0.753525 1.0286173942 −0.03893 −0.15886 −1.03693 3943 0.016177 0.318878 0.500708 39440.029472 −0.14649 −0.37317 3945 −0.15185 −0.49868 −0.607 3946 −0.09644−0.46037 −0.57596 3948 0.010157 0.279247 0.48872 3949 0.002141 −0.34666−0.2661 3950 −0.03206 −0.28804 −0.36911 3951 0.006273 0.122116 0.4146853952 −0.04024 0.176953 0.383377 3953 0.0072 −0.23691 −0.34253 39540.012744 −0.16741 −0.24655 3955 −0.019735 −0.159647 −0.33003 3957−0.00172 0.066009 0.290683 3958 0.000007 0.258618 0.366426 3959 −0.07307−0.35372 −0.42584 3960 −0.005 −0.29445 −0.89736 3962 −0.00971 −0.14007−0.77128 3963 −0.0012 −0.19036 −0.18134 3964 −0.00871 −0.31654 −0.733513965 0.007545 −0.19764 −0.31117 3967 −0.09077 −0.42429 −0.50192 39680.002684 −0.24249 −0.27393

TABLE 1b phase reporter genes SEQ ID NO log(ratio) CP log(ratio) APlog(ratio) BC 56 −0.01844 −0.2843 −0.52572 65 −0.043 −0.27935 −0.6144270 −0.02677 0.321263 0.479287 177 −0.02343 −0.25951 −0.53988 190−0.04631 −0.22027 −0.61104 199 −0.19435 −0.66091 −1.74771 1758 −0.0427−0.06237 −0.68566 1773 0.032164 0.295407 0.487261 1774 0.02296 0.3046840.561645 1786 0.014041 0.225619 0.584752 1815 0.035253 0.254518 0.530631823 0.014591 0.300107 0.456781 3925 −0.04398 −0.3128 −0.99975 3933−0.0347 −0.12523 −0.74375 3947 −0.04231 −0.53589 −1.45253 3956 −0.00856−0.16684 −0.95119

Tables 2a and 2b list a set of 386 progression genes identified bysearching for phase reporter genes after removing CD34 content (p<10⁻⁸)(the “progression geneset”). The CD34 content is removed by subtractingthe expression level of each gene in a sample of CD34+ cells from theexpression level of the gene in a tumor sample from a CML patient. Theprogression genes are identified by their SEQ ID NOs in Tables 2a and2b. Information for these genes is presented in Table 8. Table 2a listsprogression genes that were not disclosed in U.S. Patent ApplicationPublication 2003/01044026 A1, dated Jun. 5, 2003. Table 2b listsprogression genes that were also identified in U.S. Patent ApplicationPublication 2003/01044026 A1, dated Jun. 5, 2003. Tables 2a and 2b alsolisted for each gene the log ratio of CD34+(−) expression level of thegene (i.e., the expression level of the gene in a tumor sample from aCML patient minus the expression level of the gene in a sample of CD34+cells) in samples from patients of a particular phase (e.g., CP, AP, orBC) versus CD34+(−) expression level of the gene in a pool of CML bonemarrow samples from chronic phase patients. Each log ratio column thuscontains expression levels of markers for a particular phase.

TABLE 2a progression genes SEQ ID NO log(ratio) CP log(ratio) APlog(ratio) BC 2 −0.013036 0.331191 0.13619 22 −0.027625 0.25124 0.29716844 −0.008283 −0.175784 −0.35176 74 −0.018621 0.110352 −0.541362 750.012898 −0.15485 −0.081578 98 −0.0065 0.226199 0.384576 118 0.02350.413795 0.572899 120 −0.068801 −0.238346 −0.788486 123 −0.0147760.153884 0.315337 127 0.014361 0.2732 0.196317 146 −0.062898 −0.026859−0.467529 166 −0.008117 −0.02223 −0.588809 192 −0.03375 −0.376045−0.824014 201 −0.046038 0.745451 0.938831 252 −0.011159 −0.181168−0.338022 260 −0.014983 0.169381 0.378207 261 0.002136 −0.0139390.252784 277 −0.059071 0.153895 −0.707755 282 −0.011292 0.2468310.217263 300 −0.015553 0.264616 0.213715 312 −0.006268 −0.169392−0.415121 321 0.017293 0.264073 0.351815 329 0.015519 −0.110525−0.132442 348 0.003377 0.292866 0.385025 359 0.011735 −0.238758−0.159133 361 0.0199 −0.29195 −0.308127 369 0.015105 −0.30705 −0.467622379 0.011972 0.153175 0.287232 382 −0.034613 0.539856 0.385649 392−0.018091 0.211741 0.151359 397 0.001911 −0.204817 −0.142157 398−0.055256 0.454774 0.463563 401 0.010902 −0.0223 −0.435077 407 0.022957−0.146156 −0.144178 408 0.000587 0.042633 0.171636 413 −0.004104−0.021944 −0.541188 432 −0.021105 0.318234 0.36938 453 0.000187−0.016503 −0.233794 462 0.015733 −0.049378 −0.203749 464 −0.007901−0.242419 −0.192786 468 −0.069818 0.055712 −0.792861 483 0.0220870.013675 −0.264371 487 −0.044506 −0.226859 −0.730255 490 0.0322250.697253 0.473438 493 0.005365 0.117615 0.279824 506 0.002222 0.2444180.413136 508 −0.001048 0.149848 0.252886 513 −0.025942 0.105185−0.589267 532 0.013898 −0.091144 −0.105794 535 −0.02973 0.31094−0.640132 549 −0.024057 −0.192808 −0.507538 562 −0.007465 −0.085295−0.451408 564 0.010706 0.16159 0.377863 565 −0.013377 0.189935 0.358398596 −0.027369 −0.300983 −0.676728 602 −0.02947 0.152602 0.288592 607−0.03208 0.163679 0.433561 629 −0.017135 0.164754 0.393246 631 −0.0059190.029702 0.182895 638 0.005995 0.158171 0.295784 641 −0.002351 0.141381−0.371398 644 0.011035 −0.188829 −0.236191 648 −0.000305 0.093990.156447 671 −0.052686 0.224817 −0.778464 678 −0.011662 −0.03032−0.483853 686 −0.044146 0.393448 0.352519 687 0.004128 0.014188 0.147004688 −0.007112 0.135577 −0.384238 692 0.01078 −0.193913 −0.339249 6940.026903 0.238728 0.198984 699 0.002836 −0.136336 −0.204499 700−0.003573 0.186663 0.111998 702 −0.004795 0.43693 0.231795 704 0.0086520.448527 0.623811 708 0.035423 −0.072534 −0.243577 710 0.00051 −0.260385−0.325256 715 −0.031368 −0.034762 −0.28179 725 0.018721 −0.110491−0.07631 727 0.011701 0.352484 0.599663 730 0.007214 −0.100867 −0.390067739 −0.021549 0.313399 0.230556 758 0.006066 0.197232 0.154028 774−0.011428 0.297906 0.460758 781 0.049464 0.661373 0.621414 789 −0.0111350.073025 0.220549 794 0.00587 −0.124811 −0.092198 852 −0.009777 0.0619130.217413 862 0.012512 0.101103 0.346959 878 −0.007159 0.624676 0.342539879 0.015292 0.310113 −0.619546 902 0.01057 0.108517 0.282889 9060.009153 0.106628 0.432846 912 −0.03355 −0.086456 −0.556116 913−0.002153 −0.162393 −0.176945 934 −0.001515 0.49437 0.349162 949−0.009006 −0.003959 −0.260665 969 0.009521 −0.194416 −0.088755 983−0.009189 −0.179037 −0.279808 984 0.003783 0.428077 −0.304577 9950.018194 0.115536 0.453015 1005 −0.004206 0.264613 0.406912 10060.013715 0.253173 −0.48171 1014 −0.027032 0.218431 0.369874 1027−0.097802 0.14838 −0.409138 1030 0.012193 −0.156904 −0.129918 10360.018457 0.150121 0.282032 1042 0.016406 0.12399 0.254155 1047 −0.0109560.160388 0.293704 1053 −0.003597 0.168234 0.188554 1065 0.0413370.356808 0.457428 1086 0.012167 0.126556 0.308808 1089 −0.0569210.265345 0.488138 1092 0.031164 0.741399 0.650443 1093 −0.0194580.265262 0.281598 1100 −0.026376 −0.107488 0.120579 1105 0.0004020.241675 0.374547 1106 0.013275 0.053145 0.284804 1111 0.006695 0.3901090.467033 1113 0.00931 −0.151037 −0.094238 1145 −0.003373 −0.121256−0.288823 1161 −0.036419 −0.112814 −0.289979 1169 0.004364 −0.149179−0.137703 1180 −0.003015 0.149485 0.243152 1181 −0.006552 0.3547430.273738 1182 −0.063925 0.133911 −0.796733 1201 −0.024631 0.061529−0.462534 1211 −0.0131 0.42541 0.389219 1227 0.003709 −0.172158−0.119982 1228 −0.001968 −0.182794 −0.15988 1234 0.003295 −0.168464−0.233929 1264 0.007382 −0.120962 −0.228059 1288 −0.025178 0.3935850.566352 1294 0.004545 0.126708 0.283647 1308 −0.051939 −0.225136−1.142094 1324 0.000802 0.195216 0.368476 1327 0.0232 0.29162 0.3307511328 0.016117 −0.125314 −0.193334 1333 −0.001615 0.157104 0.160918 1334−0.003194 0.078374 −0.585411 1352 −0.013243 −0.259131 −0.724495 13640.020286 −0.059623 −0.36669 1394 −0.038031 0.569499 0.281012 1400−0.034692 −0.392913 −0.855372 1408 0.012613 0.202286 −0.410509 14210.015803 0.301704 −0.280571 1434 0.023441 0.24849 0.404885 1465 0.0113011.119758 0.380817 1475 0.002495 −0.174538 −0.144746 1489 −0.0058250.171399 0.198891 1503 −0.010846 0.33961 0.344346 1538 0.008774 0.2504970.380736 1544 −0.001566 −0.118486 −0.225612 1565 0.003841 −0.24087−0.188087 1586 −0.05968 0.131214 0.231979 1596 −0.012267 0.3150770.462982 1598 −0.040336 0.405119 0.295977 1600 0.016473 0.1719370.480309 1613 0.018672 0.639835 0.686131 1615 0.003796 −0.155045−0.123787 1621 0.000743 0.182262 0.22026 1622 −0.01422 0.108504 0.4411131624 −0.003494 −0.128858 −0.416283 1631 −0.066238 0.08156 0.35517 16440.012751 0.004567 −0.256495 1653 −0.051037 0.575903 0.659891 1666−0.005018 0.304418 0.391773 1667 0.020618 −0.152906 −0.073514 16740.001052 0.230389 0.365551 1707 −0.10203 −0.508005 −0.433948 1713−0.000033 0.227119 0.293211 1723 −0.008555 −0.013157 0.311742 17260.01878 −0.134004 −0.114544 1729 0.017853 0.122885 0.403719 17400.000129 0.082648 0.202706 1744 −0.008165 0.028902 0.157605 1754−0.03329 0.24969 0.276391 1756 −0.006572 −0.090777 −0.187299 1764−0.023292 0.061919 0.439367 1765 −0.069608 0.229406 −0.942888 17690.004735 0.111816 0.380203 1772 −0.053231 0.914364 0.703125 17840.011665 0.266176 0.262102 1798 0.006863 0.125618 0.179833 1802−0.006187 −0.271892 −0.547214 1813 0.004929 0.074195 −0.38902 18220.008709 0.058535 0.172787 1851 −0.038706 0.176417 −0.585557 18540.011347 −0.148867 −0.08759 1856 0.023502 −0.039695 −0.260378 18570.001175 −0.00306 −0.260983 1864 −0.023131 −0.110894 −0.595764 19020.011275 −0.14224 −0.083923 1906 −0.018987 −0.066969 −0.26783 1910−0.014553 −0.104128 −0.202699 1927 0.016189 0.022638 −0.210103 1936−0.008747 −0.190402 −0.17087 1966 0.009815 −0.207021 −0.109949 19730.025222 0.269645 −0.254999 1997 0.000408 −0.206852 −0.093692 1998−0.027543 −0.140155 −0.699914 2024 0.002746 0.021635 0.240366 2041−0.006546 0.162101 0.390622 2042 0.003359 −0.068862 −0.130822 20540.003287 0.188219 0.311283 2056 0.017212 −0.089889 −0.160576 2059−0.020181 1.117376 0.593213 2067 −0.034481 −0.314757 −0.571005 20690.020052 −0.126164 −0.092528 2084 −0.030024 0.35537 0.651561 21160.013573 −0.038963 −0.25063 2121 −0.071015 0.041386 −0.850915 2127−0.042666 0.689794 0.248637 2132 −0.001535 0.140887 0.196882 2136−0.016679 0.5014 0.158751 2148 0.007504 −0.089503 −0.424451 2162−0.018781 −0.151041 −0.25681 2196 0.001252 −0.045446 −0.145241 21970.011939 0.082814 0.421803 2211 0.016656 −0.118424 −0.17814 2218−0.001994 0.132273 0.102983 2222 −0.080043 0.129091 0.187538 22470.014934 −0.139989 −0.120912 2248 −0.012664 0.324801 0.485921 22590.009135 0.109045 −0.390417 2276 0.010096 −0.162022 −0.120129 22770.013334 0.571954 −0.227756 2282 0.003573 −0.28411 −0.296893 2286−0.00426 −0.361198 −0.342302 2298 −0.042053 −0.27671 −0.589169 23020.008627 −0.135924 −0.184813 2310 −0.001488 −0.154965 −0.151611 23340.022782 0.118742 0.155021 2344 −0.046131 −0.043556 0.354686 23730.013698 0.020747 −0.300319 2388 −0.057599 0.240909 0.4755 2392 0.007643−0.159192 −0.126831 2398 −0.04217 0.124478 −0.490219 2414 0.0062470.039279 0.231344 2458 −0.047592 −0.021181 0.62265 2464 0.0094920.497028 0.550105 2465 −0.061732 0.844778 0.746645 2474 −0.0105350.317139 0.32638 2479 0.009625 −0.032207 −0.206553 2482 0.0077130.134365 0.22816 2486 0.008277 −0.165135 −0.505359 2494 −0.008876−0.013903 −0.345788 2495 0.023159 −0.11675 −0.103801 2501 0.024313−0.133841 −0.10317 2517 0.010041 −0.026346 −0.284518 2541 0.001637−0.123709 −0.165061 2555 0.009862 −0.295888 −0.195271 2561 0.0034410.143297 0.393623 2563 −0.001684 −0.157035 −0.180935 2567 0.0187740.481516 0.617251 2580 0.001717 0.072093 0.449871 2584 −0.1085110.237285 0.358945 2591 −0.014377 0.016583 0.170925 2599 −0.0043140.138559 −0.449886 2603 0.011638 −0.148946 −0.141157 2606 −0.008722−0.002843 −0.263652 2612 0.006823 −0.083968 −0.181774 2627 0.033377−0.002066 −0.307558 2631 −0.091338 −0.170022 −1.015137 2637 0.000709−0.02223 −0.36686 2654 −0.018035 −0.080645 −0.380195 2659 0.0229760.537017 0.816212 2664 −0.002476 −0.035144 −0.354387 2696 0.0616990.295673 0.624181 2698 −0.008783 −0.162188 −0.319096 2699 0.021373−0.029099 −0.143444 2700 0.004112 0.278744 0.204271 2707 0.014731−0.005959 −0.192094 2750 0.007282 −0.224306 −0.335665 2769 −0.0853570.275787 −0.772084 2772 0.017216 −0.120145 −0.343286 2775 −0.0116730.769212 0.451896 2810 0.004075 −0.190069 −0.240619 2811 0.009903−0.176453 −0.085968 2813 0.003336 0.202659 0.191714 2815 0.0063030.092394 0.150836 2824 0.00192 −0.131874 −0.166371 2835 0.020297−0.126422 −0.206971 2856 0.006157 −0.130875 −0.287515 2864 −0.0125840.112957 0.202569 2865 0.002638 −0.150304 −0.265439 2868 −0.0023540.025594 0.276877 2873 −0.003375 −0.040933 −0.559433 2891 0.0129680.26685 0.212612 2897 −0.004267 0.32308 0.463093 2905 −0.045096−0.397135 −0.859917 2926 −0.005235 0.098392 0.200836 2931 0.0249670.193228 0.410268 2936 0.024484 −0.182182 −0.112346 2938 0.01805−0.289863 −0.273244 2946 0.005996 −0.125692 −0.084214 2964 0.019559−0.127505 −0.385534 2965 0.007544 −0.131222 −0.15763 2972 −0.0620890.082359 0.199472 2973 0.003145 0.146062 0.413226 2976 0.007741 0.072786−0.299474 2981 −0.018057 −0.15181 −0.335472 2995 0.012536 −0.169059−0.090252 3004 −0.004586 0.054952 0.213188 3014 0.005466 −0.153481−0.203641 3022 0.015475 −0.112142 −0.208532 3059 −0.014859 0.2699370.241767 3079 −0.011007 −0.20423 −0.516356 3085 −0.007467 −0.154645−0.263535 3094 0.009534 −0.137767 −0.14642 3105 0.023282 0.3251010.254346 3120 0.0307 0.350781 −0.241198 3130 0.009997 −0.13136 −0.1439763132 0.011847 −0.085343 −0.251605 3161 0.008344 −0.156984 −0.187369 3185−0.011662 0.324166 0.476811 3194 0.002083 0.14088 0.284904 3211 0.0041570.206272 0.386628 3214 0.025459 0.102741 0.240957 3215 0.00353 −0.064073−0.167793 3228 0.017223 −0.161965 −0.0726 3237 0.002668 −0.0092350.21907 3245 −0.039738 −0.344767 −0.512409 3269 −0.033522 −0.404287−0.588228 3279 −0.059744 0.264262 0.389371 3288 −0.001709 −0.176379−0.380142 3328 −0.001545 0.072595 0.2077 3337 0.01359 0.244776 0.2081253338 −0.020347 −0.138845 −0.506552 3341 −0.049209 −0.011969 −0.4191393356 0.023516 −0.13485 −0.110476 3357 0.000456 −0.135074 −0.091856 3380−0.012204 −0.399725 −0.454969 3387 0.008267 0.330665 0.191095 3390−0.002049 0.248303 0.32703 3395 −0.006382 −0.249059 −0.201365 3402−0.084896 0.054938 0.463716 3416 −0.039529 −0.201668 −0.578439 3420−0.000395 −0.09677 −0.20635 3423 0.012558 0.087882 0.242394 3426 0.011070.146821 −0.432986 3443 −0.015748 −0.058532 −0.400899 3444 −0.0178380.112361 0.21707 3470 0.01235 0.202663 0.425686 3473 0.007791 0.2227270.486992 3477 −0.007804 −0.012007 0.180183 3496 −0.078914 0.888380.619244 3516 −0.03045 −0.252169 −0.485051 3522 0.014247 0.2556930.387975 3549 0.012122 1.072368 0.652041 3560 0.010452 0.067171 0.1678253569 0.008055 0.236448 0.463364 3571 0.012994 −0.148049 −0.087744 35790.004924 −0.17069 −0.122234 3585 −0.001411 0.203954 0.124424 35940.022686 −0.159764 −0.113605 3595 0.00889 0.778268 0.724542 3627−0.018961 −0.122255 −0.455286 3649 −0.00753 −0.075377 −0.245985 3655−0.009543 −0.030372 0.280245 3658 0.010488 −0.100563 −0.316822 3662−0.021261 −0.177479 −0.164925 3678 −0.018901 −0.069804 −0.40405 36890.008179 0.111666 0.212243 3715 0.000597 0.19448 0.237315 3720 0.0069750.316981 −0.554667 3724 −0.006756 0.02331 −0.392742 3727 −0.023638−0.142935 −0.651747 3749 0.01003 0.043979 0.215776 3751 0.029168−0.073576 −0.140182 3754 0.001496 0.107186 0.165913 3755 −0.0219190.195442 0.379175 3774 0.008601 0.081842 0.189429 3781 −0.027603−0.124679 −0.389211 3795 −0.009508 −0.235417 −0.340756 3848 0.008156−0.137025 −0.091425 3853 0.00189 −0.145487 −0.229147 3854 −0.009932−0.323309 −0.627916 3865 −0.006782 0.081835 0.099887 3869 0.026028−0.164373 −0.08952 3874 0.002977 0.004837 −0.354182 3878 −0.00536−0.135863 −0.293698 3908 0.01371 −0.080601 −0.140019 3938 0.005563−0.114606 −0.098469 3941 0.018012 0.177639 0.090444 3955 −0.019735−0.159647 −0.33003

TABLE 2b progression genes SEQ ID NO log(ratio) CP log(ratio) APlog(ratio) BC 3925 0.003797 −0.153433 −0.114664

Table 3 lists the “top ten” genes that are associated with progressionand response, independent of normal CD34+ expression, based on log 10ratio of expression compared to the chronic phase pool. These genes areidentified by their SEQ ID NOs in Table 3. Information for these genesis presented in Table 8.

TABLE 3 “top ten” genes SEQ ID NO log(ratio) CP log(ratio) AP log(ratio)BC REGULATION 902 0 0 0.599663 up 984 0 0 −0.77846 down 1334 0 0−0.94289 down 1756 0 0 −0.78849 down 1813 0 0 −0.85091 down 1973 0 0−0.79673 down 2056 0 0 −1.01514 down 2211 0 0 −0.82401 down 2561 0 00.686131 up 2810 0 0 −0.85992 down 2813 0 0 0.652041 up 2815 0 00.816212 up 2824 0 0 −1.14209 down 2864 0 0 0.651561 up 2973 0 00.746645 up 3085 0 0 −0.85537 down 3211 0 0 0.617251 up 3477 0 00.619244 up 3749 0 0 0.703125 up 3941 0 0 0.659891 up

Table 4 lists a set of 228 genes associated with imatinib resistance(the “imatinib resistance genes”). The imatinib resistance genes areidentified by their SEQ ID NOs in Table 4. Information for these genesis presented in Table 8. Table 4 also listed for each gene the log ratioof expression level of the gene in samples from patients of a particularphase (e.g., CP, AP, or BC) or IM resistance (IM) versus expressionlevel of the gene in a pool of CML bone marrow samples from chronicphase patients. Each log ratio column thus contains expression levels ofmarkers for a particular phase or IM resistance.

TABLE 4 genes associated with imatinib resistance SEQ ID NO log(ratio)CP log(ratio) AP log(ratio) BC log(ratio) IM 20 0 0 −0.38709 0.263887 280 0 −0.01912 0.265124 50 0 0 0.04967 0.383703 72 0 0 −0.03184 0.24866877 0 0 −0.1097 0.230979 91 0 0 −0.21363 0.302135 93 0 0 0.0128720.248989 97 0 0 0.084015 0.441542 124 0 0 0.230888 0.535462 134 0 0−0.03703 0.179006 150 0 0 −0.0693 0.172068 155 0 0 −0.13679 0.157108 1710 0 0.196959 0.633551 195 0 0 0.02123 0.207227 243 0 0 0.11112 0.695707254 0 0 −0.08112 0.269401 269 0 0 −0.03573 0.298949 275 0 0 −0.152510.212305 283 0 0 −0.03596 0.21647 292 0 0 0.20614 0.549719 342 0 00.208194 0.677793 371 0 0 −0.06027 0.449786 372 0 0 −0.02106 0.351234377 0 0 −0.16901 0.161438 386 0 0 −0.07531 0.180776 406 0 0 −0.067670.371699 426 0 0 −0.05036 0.281576 442 0 0 −0.14473 0.198718 456 0 0−0.05428 0.215394 459 0 0 −0.03202 0.345771 469 0 0 −0.18903 0.227286480 0 0 0.038217 0.684655 531 0 0 −0.17195 0.414879 568 0 0 −0.064140.098452 622 0 0 −0.40798 0.833497 662 0 0 −0.00884 0.217496 663 0 0−0.09438 0.107198 670 0 0 −0.17245 0.1338 709 0 0 0.187456 0.553818 7220 0 −0.11073 0.162124 768 0 0 −0.10115 0.42413 785 0 0 0.219511 0.690758796 0 0 −0.12656 0.145981 856 0 0 −0.01924 0.400575 880 0 0 −0.102360.278475 894 0 0 −0.02732 0.206984 917 0 0 −0.25561 0.212912 924 0 00.224269 0.708077 973 0 0 −0.01275 0.730765 977 0 0 −0.10317 0.400818980 0 0 −0.1785 0.286644 1008 0 0 −0.10928 0.108172 1014 0 0 0.1482440.865065 1023 0 0 0.098335 0.878985 1037 0 0 −0.33476 0.837053 1038 0 0−0.20627 0.621468 1052 0 0 −0.2069 0.236861 1059 0 0 0.148036 0.4023111074 0 0 −0.33264 0.239842 1089 0 0 0.174284 0.985452 1095 0 0 0.3046560.927005 1124 0 0 −0.07093 0.616113 1143 0 0 −0.18175 0.201291 1157 0 0−0.18174 0.21747 1170 0 0 −0.08377 0.431166 1173 0 0 −0.09515 0.5600441182 0 0 −0.45446 0.142546 1190 0 0 0.041007 0.359776 1215 0 0 −0.067810.83596 1219 0 0 −0.07224 0.165806 1224 0 0 −0.05776 0.205308 1247 0 0−0.08694 0.185421 1249 0 0 0.263515 0.605748 1267 0 0 0.263464 1.0637451323 0 0 −0.2206 0.10102 1329 0 0 −0.00537 0.436924 1331 0 0 −0.014090.755256 1336 0 0 −0.15667 0.34331 1367 0 0 −0.3207 0.489696 1379 0 0−0.17026 0.205201 1389 0 0 0.079937 0.359209 1435 0 0 0.092179 0.7221081449 0 0 −0.467 0.171956 1451 0 0 0.425181 0.859676 1478 0 0 −0.1520.122073 1482 0 0 0.111952 0.395553 1494 0 0 −0.16752 0.177726 1526 0 0−0.15569 0.166092 1534 0 0 0.10057 0.802351 1549 0 0 −0.01958 0.2622071566 0 0 −0.07228 0.314048 1591 0 0 0.253125 0.761339 1657 0 0 −0.027030.334287 1671 0 0 −0.13532 0.128801 1708 0 0 −0.03956 0.206351 1709 0 00.265264 0.510844 1731 0 0 −0.16089 0.119466 1789 0 0 −0.28125 0.2463821820 0 0 −0.42872 0.604742 1839 0 0 −0.01985 0.652489 1840 0 0 0.0572410.774482 1898 0 0 −0.39467 0.378527 1948 0 0 0.082745 0.793455 1949 0 0−0.18208 0.868135 1959 0 0 −0.22455 0.344545 1965 0 0 −0.26522 0.5698662012 0 0 −0.35247 0.31479 2033 0 0 0.040006 0.345342 2073 0 0 0.0392770.877752 2081 0 0 −0.05539 0.149592 2087 0 0 −0.29516 0.404949 2088 0 0−0.02581 0.326797 2106 0 0 −0.23592 0.332507 2126 0 0 −0.02439 0.5152672145 0 0 −0.2559 0.725553 2151 0 0 −0.01135 0.414351 2172 0 0 −0.081990.39351 2178 0 0 −0.26619 0.102312 2181 0 0 −0.06055 0.158135 2183 0 00.223605 0.977949 2189 0 0 0.216936 1.068883 2199 0 0 −0.27714 0.8402652207 0 0 −0.29681 0.440807 2228 0 0 −0.05689 0.930733 2244 0 0 −0.373350.576383 2269 0 0 −0.17482 0.171115 2285 0 0 −0.05323 0.923962 2286 0 0−0.11188 0.142335 2289 0 0 −0.31747 0.354229 2292 0 0 0.437319 0.9598552354 0 0 −0.06186 0.222863 2387 0 0 −0.60522 0.324344 2388 0 0 −0.117860.725499 2408 0 0 0.27178 0.449011 2427 0 0 −0.0812 0.174195 2437 0 00.027895 1.082811 2449 0 0 0.012028 0.297163 2479 0 0 −0.22582 0.1799892492 0 0 −0.25009 0.349156 2531 0 0 0.07276 0.662312 2545 0 0 0.0216030.945236 2553 0 0 −0.01276 0.395767 2564 0 0 −0.28345 0.250146 2568 0 0−0.10977 0.19616 2582 0 0 0.253015 0.634172 2615 0 0 0.128864 1.0137052618 0 0 −0.2905 0.559533 2629 0 0 −0.06243 0.410775 2633 0 0 −0.416920.392893 2652 0 0 0.205031 0.647252 2653 0 0 −0.00396 0.377357 2660 0 0−0.53433 0.393617 2665 0 0 0.062554 0.686441 2666 0 0 0.017231 0.2766122686 0 0 0.074055 0.352962 2697 0 0 0.142879 0.722647 2756 0 0 0.0338830.281303 2780 0 0 −0.43199 0.457222 2802 0 0 0.032077 0.248953 2807 0 00.088818 0.865409 2828 0 0 0.375805 0.936957 2844 0 0 −0.10182 0.1932852879 0 0 −0.11063 0.376181 2896 0 0 −0.12602 0.433851 2942 0 0 0.0383290.261638 2955 0 0 0.337985 0.616413 2977 0 0 0.006318 0.640784 2980 0 0−0.06256 0.752042 2984 0 0 −0.0839 0.535325 2989 0 0 −0.04767 0.232912994 0 0 −0.12413 0.24541 3004 0 0 −0.22221 0.402371 3015 0 0 −0.384680.767185 3040 0 0 −0.15874 0.553807 3051 0 0 −0.16014 0.258388 3095 0 0−0.23449 0.453399 3145 0 0 0.046709 0.349592 3149 0 0 −0.07479 0.131843172 0 0 −0.09216 0.235379 3178 0 0 −0.16051 0.189495 3181 0 0 −0.181230.657828 3183 0 0 −0.08563 0.644291 3234 0 0 −0.09319 0.622993 3239 0 0−0.15225 0.543178 3263 0 0 −0.09885 0.51508 3267 0 0 −0.0802 0.2470873272 0 0 −0.06519 0.20193 3284 0 0 −0.39928 0.564677 3317 0 0 0.0422570.663222 3324 0 0 −0.0387 0.202691 3334 0 0 −0.14218 0.402162 3342 0 00.094368 0.377785 3360 0 0 −0.18153 0.352019 3370 0 0 −0.07291 0.1546293373 0 0 0.266208 1.01143 3378 0 0 0.154822 0.471737 3389 0 0 0.0962150.292396 3402 0 0 0.166222 0.929501 3433 0 0 −0.08958 0.164089 3476 0 0−0.02612 0.185903 3479 0 0 −0.23806 0.307206 3482 0 0 0.017378 0.2675813546 0 0 0.071637 0.321201 3554 0 0 −0.10865 0.21563 3620 0 0 −0.181830.230787 3632 0 0 0.04804 0.247622 3677 0 0 −0.14473 0.201314 3683 0 00.00301 0.2633 3686 0 0 −0.03852 0.375431 3692 0 0 −0.59334 0.4079063711 0 0 −0.07697 0.1336 3725 0 0 −0.1157 0.688963 3746 0 0 −0.096860.406243 3765 0 0 −0.38459 0.568063 3785 0 0 −0.02761 0.586677 3793 0 0−0.01682 0.432956 3800 0 0 0.093978 0.693084 3804 0 0 0.149344 0.9638173812 0 0 0.078875 0.719019 3836 0 0 0.245725 0.62927 3876 0 0 −0.103770.245747 3891 0 0 0.056743 0.30804 3905 0 0 −0.18947 0.77305 3935 0 0−0.1837 0.688495 3939 0 0 −0.13203 0.177443 3946 0 0 −0.57596 0.1199573966 0 0 −0.14854 0.290791

Tables 5a and 5b list 386 target genes, which are differentiallyexpressed between CML blast crisis and normal immature CD34+ cells(p<0.1%) (the “target geneset”). The target genes are identified bytheir SEQ ID NOs in Tables 5a and 5b. Information for these genes ispresented in Table 8. Table 5a lists target genes that that were notdisclosed in U.S. Patent Application Publication 2003/01044026 A1, datedJun. 5, 2003. Table 5b lists target genes that were also identified inU.S. Patent Application Publication 2003/01044026 A1, dated Jun. 5,2003.

TABLE 5a CML target genes SEQ ID NO 2 8 51 74 88 99 105 109 116 142 146158 174 184 185 191 204 246 252 261 267 298 309 312 321 337 343 359 365370 379 390 393 432 444 483 490 493 494 495 503 506 522 562 564 565 571576 596 600 602 605 607 615 628 629 631 638 644 659 664 665 675 676 688700 701 727 728 730 741 745 759 766 781 788 790 809 813 843 840 841 845847 873 878 884 900 902 906 908 915 934 960 962 983 1000 1012 1014 10201027 1036 1051 1054 1067 1089 1093 1106 1112 1132 1138 1140 1145 11581160 1161 1164 1165 1183 1188 1197 1202 1223 1245 1254 1288 1300 13061308 1311 1325 1331 1334 1346 1352 1380 1400 1409 1410 1411 1415 14161440 1441 1446 1452 1456 1464 1472 1489 1495 1500 1502 1503 1522 15271532 1534 1575 1596 1608 1614 1643 1652 1674 1689 1711 1712 1713 17241728 1756 1757 1762 1767 1772 1781 1785 1798 1799 1800 1802 1803 18131828 1849 1870 1873 1893 1910 1926 1927 1944 1990 1991 1998 2007 20112023 2032 2040 2042 2056 2064 2082 2085 2101 2104 2136 2161 2162 21742188 2200 2206 2211 2212 2213 2218 2224 2248 2252 2253 2266 2279 23042310 2312 2313 2320 2329 2356 2372 2388 2406 2442 2454 2462 2469 24792505 2525 2534 2554 2561 2563 2565 2567 2591 2600 2631 2632 2649 26542658 2664 2665 2670 2676 2696 2699 2721 2726 2734 2739 2766 2775 27772788 2810 2824 2825 2830 2842 2862 2863 2864 2892 2894 2900 2903 29212928 2938 2953 2964 2967 2981 3003 3019 3020 3027 3029 3047 3048 30673075 3085 3093 3094 3097 3103 3136 3185 3191 3194 3196 3215 3222 32383240 3241 3245 3248 3254 3279 3312 3329 3339 3348 3361 3364 3373 33803395 3396 3398 3400 3402 3428 3456 3462 3470 3500 3514 3533 3538 35553569 3582 3583 3611 3628 3640 3642 3646 3650 3655 3658 3685 3689 36963718 3755 3763 3792 3844 3845 3849 3857 3880 3901 3915 3937 3940 3955

TABLE 5b CML target genes SEQ ID NO log(ratio) BC 1776 0 3961 0

Genes that are not listed in Table 1a or 1b but which are functionalequivalents of any gene listed in Table 1a or 1b can also be used withor in place of the gene listed in the table. A functional equivalent ofa gene A refers to a gene that encodes a protein or mRNA that at leastpartially overlaps in physiological function in the cell to that of theprotein or mRNA of gene A.

In various specific embodiments, different numbers and subcombinationsof the genes listed in Tables 1a and/or 1b are selected as the markerset, whose profile is used in the methods of the invention, as describedin Section 5.2., infra. In various embodiments, all or a subset of thosegenes listed in each of Tables 2a and/or 2b or Table 3, supra, or theirrespective functional equivalents are used.

In one embodiment, one or more genes that cluster together with one ormore genes listed in a table can be selected to represent the clustersuch that the marker set contains genes representing a plurality ofdifferent clusters.

In a specific embodiment, measurements of gene products of the genes,respectively, shown in Tables 2a and/or 2b, or their respectivefunctional equivalents, are used for CML progression evaluation. In aparticular embodiment, measurements of gene products of all or at least5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100 or 200 of the geneslisted in Tables 2a and/or 2b are used.

In another embodiment, measurements of the gene products of the set of20 genes shown in Table 3 (which is a subset of the genes listed inTable 2a and Table 5a) or their respective functional equivalents areused CML progression evaluation. In a particular embodiment,measurements of gene products of all or at least 5, 10, 15 or 20 of thegenes listed in Table 3 are used.

In another embodiment, measurements of the gene products of the set of10 up-regulated genes shown in Table 3 or their respective functionalequivalents are used CML progression evaluation. In a particularembodiment, measurements of gene products of all or at least 5, 6, 7, 8,9 or all 10 of the up-regulated genes listed in Table 3 are used.

In another embodiment, measurements of the gene products of the set of10 down-regulated genes shown in Table 3 or their respective functionalequivalents are used CML progression evaluation. In a particularembodiment, measurements of gene products of all or at least 5, 6, 7, 8,9 or all 10 of the down-regulated genes listed in Table 3 are used.

In still another embodiment, measurements of the genes, respectively,shown in Table 4 or their respective functional equivalents are used fordetermining imatinib resistance in a patient. In a particularembodiment, measurements of gene products of all or at least 5, 10, 15,20, 25, 30, 40, 50, 60, 70, 80, 90, 100 or 200 of the genes listed inTable 4 are used. In a specific embodiment, imatinib resistance isdetermined according to the measurements of gene products of all or atleast 5, 6, 7, or 8 of the genes selected from the group consisting ofserine threonine kinases CTRL, MAP21K14, CLK3, MAP kinase MKNK2, thetyrosine kinase oncogene FYN, TCF7 (a putatively T cell specifictranscription factor), guanine nucleotide binding proteins GNAZ andGNG11, and the MAF.

The invention also provides sets of promoter controlled genes,measurements of which can be used for evaluating the progression of CMLin a patient. In one embodiment, measurements of the gene products ofgenes that are controlled by one or more of the promoters shown in Table6 or their respective functional equivalents are used for evaluating CMLprogression. In a particular embodiment, measurements of gene productscontrolled by a promoter selected from the group consisting of set ofpromoters shown in Table 6 or their respective functional equivalentsare used.

TABLE 6 Promoters associated with CML progression EXPEC- PROMOTERP-VALUE TATION SOURCE SPECIES MZF_1-4 0 0 Genes with common Homopromoter sites sapiens S8 1.22E−12 7.69E−11 Genes with common Homopromoter sites sapiens deltaEF1 5.87E−11 3.70E−09 Genes with common Homopromoter sites sapiens SPI-B 1.48E−10 9.35E−09 Genes with common Homopromoter sites sapiens Yin-Yang 1.48E−09 9.30E−08 Genes with common Homopromoter sites sapiens Ahr-ARNT 1.60E−09 1.01E−07 Genes with common Homopromoter sites sapiens MZF_5-13 1.26E−06 7.96E−05 Genes with common Homopromoter sites sapiens c-MYB_1 5.10E−06 0.000321 Genes with common Homopromoter sites sapiens

The invention provides methods for identifying a set of genes forevaluating stage/progression of CML. The methods make use of measuredexpression profiles of a plurality of genes (e.g., measurements ofabundance levels of the corresponding gene products) in bone marrow orblood samples from a plurality of patients whose CML stage/progressionstatus are known. As used herein, a patient is animal inflicted withCML. The patient can be but is not limited to a human, or, in aveterinary context, from non-human animals such as ruminants, horses,swine or sheep, or from domestic companion animals such as felines andcanines. In one embodiment, for each of the plurality of genes a metricof correlation between expression level of the gene and survival outcomein the plurality of CML patients is determined. One or more genes arethen selected based on their metrics of correlation.

Progression markers can be obtained by identifying genes whoseexpression levels are significantly different across CML patients ofdifferent phases of CML. In preferred embodiments, genes whoseexpression levels exhibit differences across different phrase groups toat least a predetermined level are selected as the genes whoseexpression levels correlate with CML phases. In one embodiment, theexpression level differences among patients of different CML phases areevaluated using ANOVA. In one embodiment, a gene is selected if thep-value of the gene corresponds to a predetermined significance level,e.g., a p-value less than 10⁻¹¹.

The invention also provides a computer system comprising a processor,and a memory coupled to said processor and encoding one or moreprograms, wherein said one or more programs cause the processor to carryout a method described above.

The invention also provides a computer program product for use inconjunction with a computer having a processor and a memory connected tothe processor, said computer program product comprising a computerreadable storage medium having a computer program mechanism encodedthereon, wherein said computer program mechanism may be loaded into thememory of said computer and cause said computer to carry out a methoddescribed above.

5.2. Methods of Evaluating CML Progression and Responses

The invention provides methods for determining the stage or progressionstatus in a CML patient using a measured marker profile comprisingmeasurements of the gene products of genes, e.g., the sets of genesdescribed in Section 5.1., supra.

5.2.1. Methods for Evaluating Progression Based on Expression Profiles

In preferred embodiments, the methods of the invention use a progressionclassifier, also called a classifier, for predicting CML progressionand/or responsiveness to imatinib mesylate in a patient. The progressionclassifier can be based on any appropriate pattern recognition methodthat receives an input comprising a marker profile and provides anoutput comprising data indicating which phase the patient belongs. Theprogression classifier can be trained with training data from a trainingpopulation of CML patients. Typically, the training data comprise foreach of the CML patients in the training population a training markerprofile comprising measurements of respective gene products of aplurality of genes in a suitable sample taken from the patient and CMLprogression information. In a preferred embodiment, the trainingpopulation comprises patients from each of the different stages of CML,i.e., CP-CML, ADV-CML, or AP-CML and BC-CML. In another preferredembodiment, the training population comprises patients from each of thedifferent IM response groups, i.e., IM resistant and IM responsive.

In preferred embodiments, the progression classifier can be based on aclassification (pattern recognition) method described below, e.g.,profile similarity (Section 5.2.1.1., infra); artificial neural network(Section 5.2.1.2., infra); support vector machine (SVM, Section5.2.1.3., infra); logic regression (Section 5.2.1.4., infra), linear orquadratic discriminant analysis (Section 5.2.1.5., infra), decisiontrees (Section 5.2.1.6., infra), clustering (Section 5.2.1.7., infra),principal component analysis (Section 5.2.1.8., infra), nearest neighborclassifier analysis (Section 5.2.1.9., infra). Such progressionclassifiers can be trained with the training population using methodsdescribed in the relevant sections, infra.

The marker profile can be obtained by measuring the plurality of geneproducts in a CML cell sample from the patient using a method known inthe art, e.g., a method described in Section 5.2.4-5.2.5., infra.

Various known statistical pattern recognition methods can be used inconjunction with the present invention. A progression classifier basedon any of such methods can be constructed using the marker profiles andprogression data of training patients. Such a progression classifier canthen be used to evaluate the progression status of a CML patient basedon the patient's marker profile. The methods can also be used toidentify markers that discriminate between different progression statusand/or imatinib resistance using a marker profile and progression and/orimatinib resistance data of training patients. For simplicity, themethods are often discussed with respect to evaluation of theprogression status. It will be understood by a person skilled in the artthat the methods are equally applicable to evaluation of IMresponsiveness.

5.2.1.1. Profile Matching

A patient's CML stage or progression status can be evaluated bycomparing a marker profile obtained in a suitable sample from thepatient with a marker profile that is representative of a particular CMLphase. Such a marker profile is also termed a “template profile” or a“template.” The degree of similarity to such a template profile providesan evaluation of the patient's CML stage or progression status. If thedegree of similarity of the patient marker profile and a templateprofile is above a predetermined threshold, the patient is assigned aCML phase or progression status represented by the template. Forexample, a patient's CML stage or progression status can be evaluated bycomparing a marker profile of the patient to a predetermined templateprofile corresponding to a certain CML stage or progression status,e.g., an ADV-CML template comprising measurements of the plurality ofmarkers which are representative of levels of the markers in a pluralityof advanced phase patients or a CP-CML template comprising measurementsof the plurality of markers which are representative of levels of themarkers in a plurality of chronic phase patients.

In one embodiment, the similarity is represented by a correlationcoefficient between the patient's profile and the template. In oneembodiment, a correlation coefficient above a correlation thresholdindicates a high similarity, whereas a correlation coefficient below thethreshold indicates a low similarity.

In a specific embodiment, P_(i) measures the similarity between thepatient's profile {right arrow over (y)} and a template profile, e.g., atemplate profile comprising measurements of marker gene productsrepresentative of measurements of marker gene products of a level ofprogression of CML, e.g., the CP-CML template {right arrow over(z)}_(CP) or the ADV-CML template {right arrow over (z)}_(ADV). Such acoefficient, P_(i), can be calculated using the following equation:

P _(i)=({right arrow over (z)} _(i) ·{right arrow over (y)})/(∥{rightarrow over (z)} _(i) ∥·∥{right arrow over (y)}∥)

where i designates the ith template. For example, i is CP for CP-CMLtemplate. Thus, in one embodiment, {right arrow over (y)} is classifiedas a CP-CML profile if P_(CP) is greater than a selected correlationthreshold. In another embodiment, {right arrow over (y)} is classifiedas an ADV-CML profile if P_(ADV) is greater than a selected correlationthreshold. In preferred embodiments, the correlation threshold is set as0.3, 0.4, 0.5 or 0.6. In another embodiment, {right arrow over (y)} isclassified as a CP-CML profile if P_(CP) is greater than P_(ADV),whereas {right arrow over (y)} is classified as a ADV-CML profile ifP_(CP) is less than P_(ADV).

In another embodiment, the correlation coefficient is a weighted dotproduct of the patient's profile {right arrow over (y)} and a templateprofile, in which measurements of each different marker is assigned aweight.

In another embodiment, similarity between a patient's profile and atemplate is represented by a distance between the patient's profile andthe template. In one embodiment, a distance below a given valueindicates high similarity, whereas a distance equal to or greater thanthe given value indicates low similarity.

In one embodiment, the Euclidian distance according to the formula

D _(i) =∥{right arrow over (y)}−{right arrow over (z)} _(i)∥

is used, where D_(i) measures the distance between the patient's profile{right arrow over (y)} and a template profile comprising measurements ofmarker gene products representative of measurements of marker geneproducts of a level of progression of CML, e.g., the CP-CML template{right arrow over (z)}_(CP), the ADV-CML template {right arrow over(z)}_(ADV) or the AP-CML template {right arrow over (z)}_(AP) or BC-CMLtemplate {right arrow over (z)}_(Bc). In other embodiments, theEuclidian distance is squared to place progressively greater weight oncellular constituents that are further apart. In alternativeembodiments, the distance measure D_(i) is the Manhattan distanceprovide by

$D_{i} = {\sum\limits_{n}{{{y(n)} - {z_{i}(n)}}}}$

where y(n) and z_(i)(n) are respectively measurements of the nth markergene product in the patient's profile {right arrow over (y)} and atemplate profile.

In another embodiment, the distance is defined as D_(i)=1−P_(i) whereP_(i) is the correlation coefficient or normalized dot product asdescribed above.

In still other embodiments, the distance measure may be the Chebychevdistance, the power distance, and percent disagreement, all of which arewell known in the art.

A distance based similarity measure is particularly useful forclassifying advanced phase CML patients as either AP-CML or BC-CML sincethe marker profiles of AP-CML and BC-CML differ from each other in aquantitative rather than qualitative manner. Thus, in one embodiment,the invention provides a method for classifying an advanced phase CMLpatient as either AP-CML or BC-CML by comparing the distances between amarker profile of the patient with an AP-CML template and a BC-CMLtemplate, and classifying the patient as either AP-CML or BC-CML if thedistance to the corresponding template is smaller.

A person skilled in the art would understand that the above describedmethods can be applied to expression profiles of IM resistance genes forevaluation of IM responsiveness. For example, the methods can be used tocompare a patient expression profile to IM resistance template and IMresponsive template by calculating a P_(i) measuring the similaritybetween the patient's profile {right arrow over (y)} and the IMresistance template comprising measurements of marker gene productsrepresentative of measurements of marker gene products in IM resistantpatients, {right arrow over (z)}_(resist), and/or IM responsive templatecomprising measurements of marker gene products representative ofmeasurements of marker gene products in IM responsive patients, {rightarrow over (z)}_(resp). Such a coefficient, P_(i), can be calculatedusing the equation described above.

5.2.1.2. Artificial Neural Network

In some embodiments, a neural network is used to classify a patientmarker profile. The neural network takes the patient marker profile asan input and generates an output comprising the progression statusand/or IM responsiveness. A neural network can be constructed for aselected set of molecular markers of the invention. A neural network isa two-stage regression or classification model. A neural network has alayered structure that includes a layer of input units (and the bias)connected by a layer of weights to a layer of output units. Forregression, the layer of output units typically includes just one outputunit. However, neural networks can handle multiple quantitativeresponses in a seamless fashion.

In multilayer neural networks, there are input units (input layer),hidden units (hidden layer), and output units (output layer). There is,furthermore, a single bias unit that is connected to each unit otherthan the input units. Neural networks are described in Duda et al.,2001, Pattern Classification, Second Edition, John Wiley & Sons, Inc.,New York; and Hastie et al., 2001, The Elements of Statistical Learning,Springer-Verlag, New York.

The basic approach to the use of neural networks is to start with anuntrained network, present a training pattern, e.g., marker profilesfrom training patients, to the input layer, and to pass signals throughthe net and determine the output, e.g., the status of progression and/orthe status of imatinib resistance in the training patients, at theoutput layer. These outputs are then compared to the target values; anydifference corresponds to an error. This error or criterion function issome scalar function of the weights and is minimized when the networkoutputs match the desired outputs. Thus, the weights are adjusted toreduce this measure of error. For regression, this error can besum-of-squared errors. For classification, this error can be eithersquared error or cross-entropy (deviation). See, e.g., Hastie et al.,2001, The Elements of Statistical Learning, Springer-Verlag, New York.

Three commonly used training protocols are stochastic, batch, andon-line. In stochastic training, patterns are chosen randomly from thetraining set and the network weights are updated for each patternpresentation. Multilayer nonlinear networks trained by gradient descentmethods such as stochastic back-propagation perform a maximum-likelihoodestimation of the weight values in the model defined by the networktopology. In batch training, all patterns are presented to the networkbefore learning takes place. Typically, in batch training, severalpasses are made through the training data. In online training, eachpattern is presented once and only once to the net.

In some embodiments, consideration is given to starting values forweights. If the weights are near zero, then the operative part of thesigmoid commonly used in the hidden layer of a neural network (see,e.g., Hastie et al., 2001, The Elements of Statistical Learning,Springer-Verlag, New York) is roughly linear, and hence the neuralnetwork collapses into an approximately linear model. In someembodiments, starting values for weights are chosen to be random valuesnear zero. Hence the model starts out nearly linear, and becomesnonlinear as the weights increase. Individual units localize todirections and introduce nonlinearities where needed. Use of exact zeroweights leads to zero derivatives and perfect symmetry, and thealgorithm never moves. Alternatively, starting with large weights oftenleads to poor solutions.

Since the scaling of inputs determines the effective scaling of weightsin the bottom layer, it can have a large effect on the quality of thefinal solution. Thus, in some embodiments, at the outset all expressionvalues are standardized to have mean zero and a standard deviation ofone. This ensures all inputs are treated equally in the regularizationprocess, and allows one to choose a meaningful range for the randomstarting weights. With standardization inputs, it is typical to takerandom uniform weights over the range [−0.7, +0.7].

A recurrent problem in the use of networks having a hidden layer is theoptimal number of hidden units to use in the network. The number ofinputs and outputs of a network are determined by the problem to besolved. In the present invention, the number of inputs for a givenneural network can be the number of molecular markers in the selectedset of molecular markers of the invention. The number of output for theneural network will typically be just one. However, in some embodimentmore than one output is used so that more than just two states can bedefined by the network. If too many hidden units are used in a neuralnetwork, the network will have too many degrees of freedom and istrained too long, there is a danger that the network will overfit thedata. If there are too few hidden units, the training set cannot belearned. Generally speaking, however, it is better to have too manyhidden units than too few. With too few hidden units, the model mightnot have enough flexibility to capture the nonlinearities in the data;with too many hidden units, the extra weight can be shrunk towards zeroif appropriate regularization or pruning, as described below, is used.In typical embodiments, the number of hidden units is somewhere in therange of 5 to 100, with the number increasing with the number of inputsand number of training cases.

One general approach to determining the number of hidden units to use isto apply a regularization approach. In the regularization approach, anew criterion function is constructed that depends not only on theclassical training error, but also on classifier complexity.Specifically, the new criterion function penalizes highly complexmodels; searching for the minimum in this criterion is to balance erroron the training set with error on the training set plus a regularizationterm, which expresses constraints or desirable properties of solutions:

J=J _(pat) +λJ _(reg).

The parameter λ is adjusted to impose the regularization more or lessstrongly. In other words, larger values for λ will tend to shrinkweights towards zero: typically cross-validation with a validation setis used to estimate λ. This validation set can be obtained by settingaside a random subset of the training population. Other forms of penaltycan also be used, for example the weight elimination penalty (see, e.g.,Hastie et al., 2001, The Elements of Statistical Learning,Springer-Verlag, New York).

Another approach to determine the number of hidden units to use is toeliminate—prune—weights that are least needed. In one approach, theweights with the smallest magnitude are eliminated (set to zero). Suchmagnitude-based pruning can work, but is nonoptimal; sometimes weightswith small magnitudes are important for learning and training data. Insome embodiments, rather than using a magnitude-based pruning approach,Wald statistics are computed. The fundamental idea in Wald Statistics isthat they can be used to estimate the importance of a hidden unit(weight) in a model. Then, hidden units having the least importance areeliminated (by setting their input and output weights to zero). Twoalgorithms in this regard are the Optimal Brain Damage (OBD) and theOptimal Brain Surgeon (OBS) algorithms that use second-orderapproximation to predict how the training error depends upon a weight,and eliminate the weight that leads to the smallest increase in trainingerror.

Optimal Brain Damage and Optimal Brain Surgeon share the same basicapproach of training a network to local minimum error at weight w, andthen pruning a weight that leads to the smallest increase in thetraining error. The predicted functional increase in the error for achange in full weight vector δw is:

${\delta \; J} = {{{\left( \frac{\partial J}{\partial w} \right)^{t} \cdot \delta}\; w} + {\frac{1}{2}\delta \; {w^{t} \cdot \frac{\partial^{2}J}{\partial w^{2}} \cdot \delta}\; w} + {O\left( {{\delta \; w}}^{3} \right)}}$

where

$\frac{\partial^{2}J}{\partial w^{2}}$

is the Hessian matrix. The first term vanishes because we are at a localminimum in error; third and higher order terms are ignored. The generalsolution for minimizing this function given the constraint of deletingone weight is:

${\delta \; w} = {{{- \frac{w_{q}}{\left\lbrack H^{- 1} \right\rbrack_{qq}}}{H^{- 1} \cdot u_{q}}\mspace{14mu} {and}\mspace{14mu} L_{q}} = {\frac{1}{2} - \frac{w_{q}^{2}}{\left\lbrack H^{- 1} \right\rbrack_{qq}}}}$

Here, u_(q) is the unit vector along the qth direction in weight spaceand L_(q) is approximation to the saliency of the weight q—the increasein training error if weight q is pruned and the other weights updatedδw. These equations require the inverse of H. One method to calculatethis inverse matrix is to start with a small value, H₀ ⁻¹=α⁻¹I, where αis a small parameter—effectively a weight constant. Next the matrix isupdated with each pattern according to

$H_{m + 1}^{- 1} = {H_{m}^{- 1} - \frac{H_{m}^{- 1}X_{m + 1}X_{m + 1}^{T}H_{m}^{- 1}}{\frac{n}{a_{m}} + {X_{m + 1}^{T}H_{m}^{- 1}x_{m + 1}}}}$

where the subscripts correspond to the pattern being presented and a_(m)decreases with m. After the full training set has been presented, theinverse Hessian matrix is given by H⁻¹=H_(n) ⁻¹. In algorithmic form,the Optimal Brain Surgeon method is:

  begin initialize n_(H), w, θ  train a reasonably large network tominimum error  do compute H⁻¹ by Eqn. 1   $\left. q^{*}\leftarrow{\arg \mspace{14mu} {\min\limits_{q}\mspace{14mu} {w_{q}^{2}\text{/}\left( {2\left\lbrack H^{- 1} \right\rbrack}_{qq} \right)\mspace{14mu} \left( {{saliency}\mspace{14mu} L_{q}} \right)}}} \right.$  $\left. w\leftarrow{w - {\frac{w_{q^{*}}}{\left\lbrack H^{- 1} \right\rbrack_{q^{*}q^{*}}}H^{- 1}e_{q^{*}}\mspace{14mu} \left( {{saliency}\mspace{14mu} L_{q}} \right)}} \right.$  until J(w) > θ  return w end

The Optimal Brain Damage method is computationally simpler because thecalculation of the inverse Hessian matrix in line 3 is particularlysimple for a diagonal matrix. The above algorithm terminates when theerror is greater than a criterion initialized to be θ. Another approachis to change line 6 to terminate when the change in J(w) due toelimination of a weight is greater than some criterion value.

In some embodiments, a back-propagation neural network (see, for exampleAbdi, 1994, “A neural network primer”, J. Biol System. 2, 247-283)containing a single hidden layer of ten neurons (ten hidden units) foundin EasyNN-Plus version 4.0 g software package (Neural Planner SoftwareInc.) is used. In a specific example, parameter values within theEasyNN-Plus program are set as follows: a learning rate of 0.05, and amomentum of 0.2. In some embodiments in which the EasyNN-Plus version4.0 g software package is used, “outlier” samples are identified byperforming twenty independently-seeded trials involving 20,000 learningcycles each.

5.2.1.3. Support Vector Machine

In some embodiments of the present invention, support vector machines(SVMs) are used to classify subjects using expression profiles of markergenes described in the present invention. The SVM takes the patientmarker profile as an input and generates an output comprising theprogression status and/or IM responsiveness. General description of SVMcan be found in, for example, Cristianini and Shawe-Taylor, 2000, AnIntroduction to Support Vector Machines, Cambridge University Press,Cambridge, Boser et al., 1992, “A training algorithm for optimal marginclassifiers, in Proceedings of the 5^(th) Annual ACM Workshop onComputational Learning Theory, ACM Press, Pittsburgh, Pa., pp. 142-152;Vapnik, 1998, Statistical Learning Theory, Wiley, New York; Duda,Pattern Classification, Second Edition, 2001, John Wiley & Sons, Inc.;Hastie, 2001, The Elements of Statistical Learning, Springer, N.Y.; andFurey et al., 2000, Bioinformatics 16, 906-914. Applications of SVM inbiological applications are described in Jaakkola et al., Proceedings ofthe 7^(th) International Conference on Intelligent Systems for MolecularBiology, AAAI Press, Menlo Park, Calif. (1999); Brown et al., Proc.Natl. Acad. Sci. 97(1):262-67 (2000); Zien et al., Bioinformatics,16(9):799-807 (2000); Furey et al., Bioinformatics, 16(10):906-914(2000)

In one approach, when a SVM is used, the gene expression data isstandardized to have mean zero and unit variance and the members of atraining population are randomly divided into a training set and a testset. For example, in one embodiment, two thirds of the members of thetraining population are placed in the training set and one third of themembers of the training population are placed in the test set. Theexpression values for a selected set of genes of the present inventionis used to train the SVM. Then the ability for the trained SVM tocorrectly classify members in the test set is determined. In someembodiments, this computation is performed several times for a givenselected set of molecular markers. In each iteration of the computation,the members of the training population are randomly assigned to thetraining set and the test set. Then, the quality of the combination ofmolecular markers is taken as the average of each such iteration of theSVM computation.

Support vector machines map a given set of binary labeled training datato a high-dimensional feature space and separate the two classes of datawith a maximum margin hyperplane. In general, this hyperplanecorresponds to a nonlinear decision boundary in the input space. LetXεR₀ ⊂

^(n) be the input vectors, yε{−1,+1} be the labels, and φ: R₀→F be themapping from input space to feature space. Then the SVM learningalgorithm finds a hyperplane (w,b) such that the quantity

$\gamma = {\min\limits_{i}{y_{i}\left\{ {{\langle{w,{\varphi \left( X_{i} \right)}}\rangle} - b} \right\}}}$

is maximized, where the vector w has the same dimensionality as F, b isa real number, and γ is called the margin. The corresponding decisionfunction is then

ƒ(X)=sign(

w,φ(X)

−b)

This minimum occurs when

$w = {\sum\limits_{i}{\alpha_{i}y_{i}{\varphi \left( X_{i} \right)}}}$

where {α_(i)} are positive real numbers that maximize

${\sum\limits_{i}\alpha_{i}} - {\sum\limits_{ij}{\alpha_{i}\alpha_{j}y_{i}y_{j}{\langle{{\varphi \left( X_{i} \right)},{\varphi \left( X_{j} \right)}}\rangle}}}$

subject to

${{\sum\limits_{i}{\alpha_{i}y_{i}}} = 0},{\alpha_{i} > 0}$

The decision function can equivalently be expressed as

${f(X)} = {{sign}\left( {\sum\limits_{i}{\alpha_{i}y_{i}\left. \langle{{\varphi\left( {X_{i},{\varphi (X)}}\rangle \right.} - b} \right)}} \right.}$

From this equation it can be seen that the α_(i) associated with thetraining point X_(i) expresses the strength with which that point isembedded in the final decision function. A remarkable property of thisalternative representation is that only a subset of the points will beassociated with a non-zero α_(i). These points are called supportvectors and are the points that lie closest to the separatinghyperplane. The sparseness of the α vector has several computational andlearning theoretic consequences. It is important to note that neitherthe learning algorithm nor the decision function needs to representexplicitly the image of points in the feature space, φ(X_(i)), sinceboth use only the dot products between such images,

φ(X_(i)),φ(X_(j))

. Hence, if one were given a function K(X,Y)=

φ(X),φ(X)

, one could learn and use the maximum margin hyperplane in the featurespace without ever explicitly performing the mapping. For eachcontinuous positive definite function K(X,Y) there exists a mapping φsuch that K(X,Y)=

φ(X),φ(X)

for all X, YεR₀ (Mercer's Theorem). The function K(X,Y) is called thekernel function. The use of a kernel function allows the support vectormachine to operate efficiently in a nonlinear high-dimensional featurespaces without being adversely affected by the dimensionality of thatspace. Indeed, it is possible to work with feature spaces of infinitedimension. Moreover, Mercer's theorem makes it possible to learn in thefeature space without even knowing φ and F. The matrix K_(ij)=

φ(X_(i)),φ(X_(j))

is called the kernel matrix. Finally, note that the learning algorithmis a quadratic optimization problem that has only a global optimum. Theabsence of local minima is a significant difference from standardpattern recognition techniques such as neural networks. For moderatesample sizes, the optimization problem can be solved with simplegradient descent techniques. In the presence of noise, the standardmaximum margin algorithm described above can be subject to overfitting,and more sophisticated techniques should be used. This problem arisesbecause the maximum margin algorithm always finds a perfectly consistenthypothesis and does not tolerate training error. Sometimes, however, itis necessary to trade some training accuracy for better predictivepower. The need for tolerating training error has led to the developmentthe soft-margin and the margin-distribution classifiers. One of thesetechniques replaces the kernel matrix in the training phase as follows:

K←K+λI

while still using the standard kernel function in the decision phase. Bytuning λ, one can control the training error, and it is possible toprove that the risk of misclassifying unseen points can be decreasedwith a suitable choice of λ.

If instead of controlling the overall training error one wants tocontrol the trade-off between false positives and false negatives, it ispossible to modify K as follows:

K←K+λD

where D is a diagonal matrix whose entries are either d⁺ or d⁻, inlocations corresponding to positive and negative examples. It ispossible to prove that this technique is equivalent to controlling thesize of the α_(i) in a way that depends on the size of the class,introducing a bias for larger α_(i) in the class with smaller d. This inturn corresponds to an asymmetric margin; i.e., the class with smaller dwill be kept further away from the decision boundary. In some cases, theextreme imbalance of the two classes, along with the presence of noise,creates a situation in which points from the minority class can beeasily mistaken for mislabelled points. Enforcing a strong bias againsttraining errors in the minority class provides protection against sucherrors and forces the SVM to make the positive examples support vectors.Thus, choosing

$d^{+} = {{\frac{1}{n^{+}}\mspace{14mu} {and}\mspace{14mu} d^{-}} = \frac{1}{n^{-}}}$

provides a heuristic way to automatically adjust the relative importanceof the two classes, based on their respective cardinalities. Thistechnique effectively controls the trade-off between sensitivity andspecificity.

In the present invention, a linear kernel can be used. The similaritybetween two marker profiles X and Y can be the dot product X·Y. In oneembodiment, the kernel is

K(X,Y)=X·Y+1

In another embodiment, a kernel of degree d is used

K(X,Y)=(X·Y+1)^(d), where d can be either 2, 3, . . .

In still another embodiment, a Gaussian kernel is used

${K\left( {X,Y} \right)} = {\exp\left( \frac{- {{X - Y}}^{2}}{2\sigma^{2}} \right)}$

where σ is the width of the Gaussian.

5.2.1.4. Logistic Regression

In some embodiments, the progression classifier is based on a regressionmodel, preferably a logistic regression model. Such a regression modelincludes a coefficient for each of the molecular markers in a selectedset of molecular markers of the invention. In such embodiments, thecoefficients for the regression model are computed using, for example, amaximum likelihood approach. In particular embodiments, molecular markerdata from two different clinical groups, e.g., chronic phase andadvanced phase or imatinib resistant and imatinib sensitive, is used andthe dependent variable is the clinical status of the patient for whichmolecular marker characteristic data are from.

Some embodiments of the present invention provide generalizations of thelogistic regression model that handle multicategory (polychotomous)responses. Such embodiments can be used to discriminate an organism intoone or three or more clinical groups, e.g., chronic phase, acceleratedphase, and blast phase. Such regression models use multicategory logitmodels that simultaneously refer to all pairs of categories, anddescribe the odds of response in one category instead of another. Oncethe model specifies logits for a certain (J-1) pairs of categories, therest are redundant. See, for example, Agresti, An Introduction toCategorical Data Analysis, John Wiley & Sons, Inc., 1996, New York,Chapter 8, which is hereby incorporated by reference.

5.2.1.5. Discriminant Analysis

Linear discriminant analysis (LDA) attempts to classify a subject intoone of two categories based on certain object properties. In otherwords, LDA tests whether object attributes measured in an experimentpredict categorization of the objects. LDA typically requires continuousindependent variables and a dichotomous categorical dependent variable.In the present invention, the expression values for the selected set ofmolecular markers of the invention across a subset of the trainingpopulation serve as the requisite continuous independent variables. Theclinical group classification of each of the members of the trainingpopulation serves as the dichotomous categorical dependent variable.

LDA seeks the linear combination of variables that maximizes the ratioof between-group variance and within-group variance by using thegrouping information. Implicitly, the linear weights used by LDA dependon how the expression of a molecular marker across the training setseparates in the two groups (e.g., a group that has CP-CML and a groupthat have ADV-CMP) and how this gene expression correlates with theexpression of other genes. In some embodiments, LDA is applied to thedata matrix of the N members in the training sample by K genes in acombination of genes described in the present invention. Then, thelinear discriminant of each member of the training population isplotted. Ideally, those members of the training population representinga first subgroup (e.g. those subjects that have CP-CML) will clusterinto one range of linear discriminant values (e.g., negative) and thosemember of the training population representing a second subgroup (e.g.those subjects that have ADV-CML) will cluster into a second range oflinear discriminant values (e.g., positive). The LDA is considered moresuccessful when the separation between the clusters of discriminantvalues is larger. For more information on linear discriminant analysis,see Duda, Pattern Classification, Second Edition, 2001, John Wiley &Sons, Inc; and Hastie, 2001, The Elements of Statistical Learning,Springer, N.Y.; Venables & Ripley, 1997, Modern Applied Statistics withs-plus, Springer, N.Y.

Quadratic discriminant analysis (QDA) takes the same input parametersand returns the same results as LDA. QDA uses quadratic equations,rather than linear equations, to produce results. LDA and QDA areinterchangeable, and which to use is a matter of preference and/oravailability of software to support the analysis. Logistic regressiontakes the same input parameters and returns the same results as LDA andQDA.

5.2.1.6. Decision Trees

In some embodiments of the present invention, decision trees are used toclassify patients using expression data for a selected set of molecularmarkers of the invention. Decision tree algorithms belong to the classof supervised learning algorithms. The aim of a decision tree is toinduce a classifier (a tree) from real-world example data. This tree canbe used to classify unseen examples which have not been used to derivethe decision tree.

A decision tree is derived from training data. An example containsvalues for the different attributes and what class the example belongs.In one embodiment, the training data is expression data for acombination of genes described in the present invention across thetraining population.

The following algorithm describes a decision tree derivation:

Tree(Examples,Class,Attributes)   Create a root node   If all Exampleshave the same Class value, give the   root this label   Else ifAttributes is empty label the root according to the   most common value  Else begin     Calculate the information gain for each attribute    Select the attribute A with highest information gain and make thisthe root attribute     For each possible value, v, of this attribute      Add a new branch below the root, corresponding to A = v       LetExamples(v) be those examples with A = v       If Examples(v) is empty,make the new branch a leaf node       labeled with the most common valueamong Examples       Else let the new branch be the tree created by       Tree(Examples(v),Class,Attributes - {A})   endA more detailed description of the calculation of information gain isshown in the following. If the possible classes v_(i) of the exampleshave probabilities P(v_(i)) then the information content I of the actualanswer is given by:

${I\left( {{P\left( v_{1} \right)},\ldots \mspace{14mu},{P\left( v_{n} \right)}} \right)} = {\sum\limits_{i = 1}^{n}{{- {P\left( v_{i} \right)}}\log_{2}{P\left( v_{i} \right)}}}$

The I-value shows how much information we need in order to be able todescribe the outcome of a classification for the specific dataset used.Supposing that the dataset contains p positive (e.g. has ADV-CML) and nnegative (e.g. has CP-CML) examples (e.g. individuals), the informationcontained in a correct answer is:

${I\left( {\frac{p}{p + n},\frac{n}{p + n}} \right)} = {{{- \frac{p}{p + n}}\log_{2}\frac{p}{p + n}} - {\frac{n}{p + n}\log_{2}\frac{n}{p + n}}}$

where log₂ is the logarithm using base two. By testing single attributesthe amount of information needed to make a correct classification can bereduced. The remainder for a specific attribute A (e.g. a gene) showshow much the information that is needed can be reduced.

${{Remainder}(A)} = {\sum\limits_{i = 1}^{v}{\frac{p_{i} + n_{i}}{p + n}{I\left( {\frac{p_{i}}{p_{i} + n_{i}},\frac{n_{i}}{p_{i} + n_{i}}} \right)}}}$

“v” is the number of unique attribute values for attribute A in acertain dataset, “i” is a certain attribute value, “p_(i)” is the numberof examples for attribute A where the classification is positive (e.g.cancer), “n_(i)” is the number of examples for attribute A where theclassification is negative (e.g. healthy).

The information gain of a specific attribute A is calculated as thedifference between the information content for the classes and theremainder of attribute A:

${{Gain}(A)} = {{I\left( {\frac{p}{p + n},\frac{n}{p + n}} \right)} - {{Remainder}(A)}}$

The information gain is used to evaluate how important the differentattributes are for the classification (how well they split up theexamples), and the attribute with the highest information.

In general there are a number of different decision tree algorithms,many of which are described in Duda, Pattern Classification, SecondEdition, 2001, John Wiley & Sons, Inc. Decision tree algorithms oftenrequire consideration of feature processing, impurity measure, stoppingcriterion, and pruning. Specific decision tree algorithms include, cutare not limited to classification and regression trees (CART),multivariate decision trees, ID3, and C4.5.

In one approach, when an exemplary embodiment of a decision tree isused, the gene expression data for a selected set of molecular markersof the invention across a training population is standardized to havemean zero and unit variance. The members of the training population arerandomly divided into a training set and a test set. For example, in oneembodiment, two thirds of the members of the training population areplaced in the training set and one third of the members of the trainingpopulation are placed in the test set. The expression values for aselect combination of genes described in the present invention is usedto construct the decision tree. Then, the ability for the decision treeto correctly classify members in the test set is determined. In someembodiments, this computation is performed several times for a givencombination of molecular markers. In each iteration of the computation,the members of the training population are randomly assigned to thetraining set and the test set. Then, the quality of the combination ofmolecular markers is taken as the average of each such iteration of thedecision tree computation.

5.2.1.7. Clustering

In some embodiments, the expression values for a selected set ofmolecular markers of the invention are used to cluster a training set.For example, consider the case in which ten genes described in thepresent invention are used. Each member m of the training populationwill have expression values for each of the ten genes. Such values froma member m in the training population define the vector:

X_(1m) X_(2m) X_(3m) X_(4m) X_(5m) X_(6m) X_(7m) X_(8m) X_(9m) X_(10m)where X_(im) is the expression level of the i^(th) gene in organism m.If there are m organisms in the training set, selection of i genes willdefine m vectors. Note that the methods of the present invention do notrequire that each the expression value of every single gene used in thevectors be represented in every single vector m. In other words, datafrom a subject in which one of the i^(th) genes is not found can stillbe used for clustering. In such instances, the missing expression valueis assigned either a “zero” or some other normalized value. In someembodiments, prior to clustering, the gene expression values arenormalized to have a mean value of zero and unit variance.

Those members of the training population that exhibit similar expressionpatterns across the training group will tend to cluster together. Aparticular combination of genes of the present invention is consideredto be a good classifier in this aspect of the invention when the vectorscluster into the trait groups found in the training population. Forinstance, if the training population includes patients with chronicphase and advanced phase CML, a clustering classifier will cluster thepopulation into two groups, with each group uniquely representing eitherchronic phase or advanced phase.

Clustering is described on pages 211-256 of Duda and Hart, PatternClassification and Scene Analysis, 1973, John Wiley & Sons, Inc., NewYork. As described in Section 6.7 of Duda, the clustering problem isdescribed as one of finding natural groupings in a dataset. To identifynatural groupings, two issues are addressed. First, a way to measuresimilarity (or dissimilarity) between two samples is determined. Thismetric (similarity measure) is used to ensure that the samples in onecluster are more like one another than they are to samples in otherclusters. Second, a mechanism for partitioning the data into clustersusing the similarity measure is determined.

Similarity measures are discussed in Section 6.7 of Duda, where it isstated that one way to begin a clustering investigation is to define adistance function and to compute the matrix of distances between allpairs of samples in a dataset. If distance is a good measure ofsimilarity, then the distance between samples in the same cluster willbe significantly less than the distance between samples in differentclusters. However, as stated on page 215 of Duda, clustering does notrequire the use of a distance metric. For example, a nonmetricsimilarity function s(x, x′) can be used to compare two vectors x andx′. Conventionally, s(x, x′) is a symmetric function whose value islarge when x and x′ are somehow “similar”. An example of a nonmetricsimilarity function s(x, x′) is provided on page 216 of Duda.

Once a method for measuring “similarity” or “dissimilarity” betweenpoints in a dataset has been selected, clustering requires a criterionfunction that measures the clustering quality of any partition of thedata. Partitions of the data set that extremize the criterion functionare used to cluster the data. See page 217 of Duda. Criterion functionsare discussed in Section 6.8 of Duda.

More recently, Duda et al., Pattern Classification, 2^(nd) edition, JohnWiley & Sons, Inc. New York, has been published. Pages 537-563 describeclustering in detail. More information on clustering techniques can befound in Kaufman and Rousseeuw, 1990, Finding Groups in Data: AnIntroduction to Cluster Analysis, Wiley, New York, N.Y.; Everitt, 1993,Cluster analysis (3d ed.), Wiley, New York, N.Y.; and Backer, 1995,Computer-Assisted Reasoning in Cluster Analysis, Prentice Hall, UpperSaddle River, N.J. Particular exemplary clustering techniques that canbe used in the present invention include, but are not limited to,hierarchical clustering (agglomerative clustering using nearest-neighboralgorithm, farthest-neighbor algorithm, the average linkage algorithm,the centroid algorithm, or the sum-of-squares algorithm), k-meansclustering, fuzzy k-means clustering algorithm, and Jarvis-Patrickclustering.

5.2.1.8. Principal Component Analysis

Principal component analysis (PCA) has been proposed to analyze geneexpression data. Principal component analysis is a classical techniqueto reduce the dimensionality of a data set by transforming the data to anew set of variable (principal components) that summarize the featuresof the data. See, for example, Jolliffe, 1986, Principal ComponentAnalysis, Springer, N.Y. Principal components (PCs) are uncorrelate andare ordered such that the k^(th) PC has the kth largest variance amongPCs. The k^(th) PC can be interpreted as the direction that maximizesthe variation of the projections of the data points such that it isorthogonal to the first k−1 PCs. The first few PCs capture most of thevariation in the data set. In contrast, the last few PCs are oftenassumed to capture only the residual ‘noise’ in the data.

PCA can also be used to create a progression classifier in accordancewith the present invention. In such an approach, vectors for a selectedset of molecular markers of the invention can be constructed in the samemanner described for clustering above. In fact, the set of vectors,where each vector represents the expression values for the select genesfrom a particular member of the training population, can be considered amatrix. In some embodiments, this matrix is represented in a Free-Wilsonmethod of qualitative binary description of monomers (Kubinyi, 1990, 3DQSAR in drug design theory methods and applications, Pergamon Press,Oxford, pp 589-638), and distributed in a maximally compressed spaceusing PCA so that the first principal component (PC) captures thelargest amount of variance information possible, the second principalcomponent (PC) captures the second largest amount of all varianceinformation, and so forth until all variance information in the matrixhas been accounted for.

Then, each of the vectors (where each vector represents a member of thetraining population) is plotted. Many different types of plots arepossible. In some embodiments, a one-dimensional plot is made. In thisone-dimensional plot, the value for the first principal component fromeach of the members of the training population is plotted. In this formof plot, the expectation is that members of a first group (e.g. chronicphase patients) will cluster in one range of first principal componentvalues and members of a second group (e.g., advance phase patients) willcluster in a second range of first principal component values.

In one example, the training population comprises two groups: chronicphase patients and advanced phase patients or imatinib resistant andimatinib sensitive. The first principal component is computed using themolecular marker expression values for the select genes of the presentinvention across the entire training population data set. Then, eachmember of the training set is plotted as a function of the value for thefirst principal component. In this example, those members of thetraining population in which the first principal component is positiveare the chronic phase (or imatinib sensitive) patients and those membersof the training population in which the first principal component isnegative are advanced phase (or imatinib resistant) patients.

In some embodiments, the members of the training population are plottedagainst more than one principal component. For example, in someembodiments, the members of the training population are plotted on atwo-dimensional plot in which the first dimension is the first principalcomponent and the second dimension is the second principal component. Insuch a two-dimensional plot, the expectation is that members of eachsubgroup represented in the training population will cluster intodiscrete groups. For example, a first cluster of members in thetwo-dimensional plot will represent subjects with CP-CML, a secondcluster of members in the two-dimensional plot will represent subjectswith ADV-CML, and so forth.

In some embodiments, the members of the training population are plottedagainst more than two principal components and a determination is madeas to whether the members of the training population are clustering intogroups that each uniquely represents a subgroup found in the trainingpopulation. In some embodiments, principal component analysis isperformed by using the R mva package (Anderson, 1973, Cluster Analysisfor applications, Academic Press, New York 1973; Gordon, Classification,Second Edition, Chapman and Hall, CRC, 1999.). Principal componentanalysis is further described in Duda, Pattern Classification, SecondEdition, 2001, John Wiley & Sons, Inc.

5.2.1.9. Nearest Neighbor Classifier Analysis

Nearest neighbor classifiers are memory-based and require no model to befit. Given a query point x₀, the k training points x_((r)), r, . . . , kclosest in distance to x₀ are identified and then the point x₀ isclassified using the k nearest neighbors. Ties can be broken at random.

In some embodiments, Euclidean distance in feature space is used todetermine distance as:

d _((i)) =∥x _((i)) −x ₀∥.

Typically, when the nearest neighbor algorithm is used, the expressiondata used to compute the linear discriminant is standardized to havemean zero and variance 1. In the present invention, the members of thetraining population are randomly divided into a training set and a testset. For example, in one embodiment, two thirds of the members of thetraining population are placed in the training set and one third of themembers of the training population are placed in the test set. Profilesof a selected set of molecular markers of the invention represents thefeature space into which members of the test set are plotted. Next, theability of the training set to correctly characterize the members of thetest set is computed. In some embodiments, nearest neighbor computationis performed several times for a given combination of genes of thepresent invention. In each iteration of the computation, the members ofthe training population are randomly assigned to the training set andthe test set. Then, the quality of the combination of genes is taken asthe average of each such iteration of the nearest neighbor computation.

The nearest neighbor rule can be refined to deal with issues of unequalclass priors, differential misclassification costs, and featureselection. Many of these refinements involve some form of weightedvoting for the neighbors. For more information on nearest neighboranalysis, see Duda, Pattern Classification, Second Edition, 2001, JohnWiley & Sons, Inc; and Hastie, 2001, The Elements of StatisticalLearning, Springer, N.Y.

5.2.1.10. Evolutionary Methods

Inspired by the process of biological evolution, evolutionary methods ofclassifier design employ a stochastic search for an optimal classifier.In broad overview, such methods create several classifiers—apopulation—from measurements of gene products of the present invention.Each classifier varies somewhat from the other. Next, the classifiersare scored on expression data across the training population. In keepingwith the analogy with biological evolution, the resulting (scalar) scoreis sometimes called the fitness. The classifiers are ranked according totheir score and the best classifiers are retained (some portion of thetotal population of classifiers). Again, in keeping with biologicalterminology, this is called survival of the fittest. The classifiers arestochastically altered in the next generation—the children or offspring.Some offspring classifiers will have higher scores than their parent inthe previous generation, some will have lower scores. The overallprocess is then repeated for the subsequent generation: The classifiersare scored and the best ones are retained, randomly altered to give yetanother generation, and so on. In part, because of the ranking, eachgeneration has, on average, a slightly higher score than the previousone. The process is halted when the single best classifier in ageneration has a score that exceeds a desired criterion value. Moreinformation on evolutionary methods is found in, for example, Duda,Pattern Classification, Second Edition, 2001, John Wiley & Sons, Inc.

5.2.1.11. Bagging, Boosting and the Random Subspace Method

Bagging, boosting and the random subspace method are combiningtechniques that can be used to improve weak classifiers. Thesetechniques are designed for, and usually applied to, decision trees. Inaddition, Skurichina and Duin provide evidence to suggest that suchtechniques can also be useful in linear discriminant analysis.

In bagging, one samples the training set, generating random independentbootstrap replicates, constructs the classifier on each of these, andaggregates them by a simple majority vote in the final decision rule.See, for example, Breiman, 1996, Machine Learning 24, 123-140; and Efron& Tibshirani, An Introduction to Bootstrap, Chapman & Hall, New York,1993.

In boosting, classifiers are constructed on weighted versions of thetraining set, which are dependent on previous classification results.Initially, all objects have equal weights, and the first classifier isconstructed on this data set. Then, weights are changed according to theperformance of the classifier. Erroneously classified objects (molecularmarkers in the data set) get larger weights, and the next classifier isboosted on the reweighted training set. In this way, a sequence oftraining sets and classifiers is obtained, which is then combined bysimple majority voting or by weighted majority voting in the finaldecision. See, for example, Freund & Schapire, “Experiments with a newboosting algorithm,” Proceedings 13^(th) International Conference onMachine Learning, 1996, 148-156.

To illustrate boosting, consider the case where there are two phenotypicgroups exhibited by the population under study, phenotype 1 (e.g.,advanced phase patients), and phenotype 2 (e.g., chronic phasepatients). Given a vector of molecular markers X, a classifier G(X)produces a prediction taking one of the type values in the two valueset: {phenotype 1, phenotype 2}. The error rate on the training sampleis

$\overset{\_}{err} = {\frac{1}{N}{\sum\limits_{i = 1}^{N}{I\left( {y_{i} \neq {G\left( x_{i} \right)}} \right)}}}$

where N is the number of subjects in the training set (the sum total ofthe subjects that have either phenotype 1 or phenotype 2).

A weak classifier is one whose error rate is only slightly better thanrandom guessing. In the boosting algorithm, the weak classificationalgorithm is repeatedly applied to modified versions of the data,thereby producing a sequence of weak classifiers G_(m)(x), m,=1, 2, . .. , M. The predictions from all of the classifiers in this sequence arethen combined through a weighted majority vote to produce the finalprediction:

${G(x)} = {{sign}\left( {\sum\limits_{m = 1}^{M}{\alpha_{m}{G_{m}(x)}}} \right)}$

Here α₁, α₂, . . . , α_(M) are computed by the boosting algorithm andtheir purpose is to weigh the contribution of each respective G_(m)(x).Their effect is to give higher influence to the more accurateclassifiers in the sequence.

The data modifications at each boosting step consist of applying weightsw₁, w₂, . . . , w_(n) to each of the training observations (x_(i),y_(i)), i=1, 2, . . . , N. Initially all the weights are set tow_(i)=1/N, so that the first step simply trains the classifier on thedata in the usual manner. For each successive iteration m=2, 3, . . . ,M the observation weights are individually modified and theclassification algorithm is reapplied to the weighted observations. Atstem m, those observations that were misclassified by the classifierG_(m-1)(x) induced at the previous step have their weights increased,whereas the weights are decreased for those that were classifiedcorrectly. Thus as iterations proceed, observations that are difficultto correctly classify receive ever-increasing influence. Each successiveclassifier is thereby forced to concentrate on those trainingobservations that are missed by previous ones in the sequence.

The exemplary boosting algorithm is summarized as follows:

 1. Initialize the observation weights w_(i) = 1/N, i = 1, 2, . . . , N. 2. For m = 1 to M:   (a) Fit a classifier G_(m)(x) to the training setusing weights w_(i).   (b) Compute    ${err}_{m} = \frac{\sum\limits_{i = 1}^{N}{w_{i}{I\left( {y_{i} \neq {G_{m}\left( x_{i} \right)}} \right)}}}{\sum\limits_{i = 1}^{N}w_{i}}$ (c) Compute α_(m) = log((l − err_(m))/err_(m)).  (d) Set w_(i) ← w_(i)· exp[α_(m) · I(y_(i) ≠ G_(m)(x_(i)))], i = 1, 2, . . . , N.${3.\mspace{14mu} {Output}\mspace{14mu} {G(x)}} = {{sign}\mspace{14mu} \left\lfloor {\sum\limits_{m = 1}^{M}{\alpha_{m}{G_{m}(x)}}} \right\rfloor}$In the algorithm, the current classifier G_(m)(x) is induced on theweighted observations at line 2a. The resulting weighted error rate iscomputed at line 2b. Line 2c calculates the weight α_(m) given toG_(m)(x) in producing the final classifier G(x) (line 3). The individualweights of each of the observations are updated for the next iterationat line 2d. Observations misclassified by G_(m)(x) have their weightsscaled by a factor exp(α_(m)), increasing their relative influence forinducing the next classifier G_(m+1)/(x) in the sequence. In someembodiments, modifications of the Freund and Schapire, 1997, Journal ofComputer and System Sciences 55, pp. 119-139, boosting method are used.See, for example, Hasti et al., The Elements of Statistical Learning,2001, Springer, N.Y., Chapter 10. In some embodiments, boosting oradaptive boosting methods are used.

In some embodiments, modifications of Freund and Schapire, 1997, Journalof Computer and System Sciences 55, pp. 119-139, are used. For example,in some embodiments, feature preselection is performed using a techniquesuch as the nonparametric scoring methods of Park et al., 2002, Pac.Symp. Biocomput. 6, 52-63. Feature preselection is a form ofdimensionality reduction in which the genes that discriminate betweenclassifications the best are selected for use in the classifier. Then,the LogitBoost procedure introduced by Friedman et al., 2000, Ann Stat28, 337-407 is used rather than the boosting procedure of Freund andSchapire. In some embodiments, the boosting and other classificationmethods of Ben-Dor et al., 2000, Journal of Computational Biology 7,559-583 are used in the present invention. In some embodiments, theboosting and other classification methods of Freund and Schapire, 1997,Journal of Computer and System Sciences 55, 119-139, are used.

In the random subspace method, classifiers are constructed in randomsubspaces of the data feature space. These classifiers are usuallycombined by simple majority voting in the final decision rule. See, forexample, Ho, “The Random subspace method for constructing decisionforests,” IEEE Trans Pattern Analysis and Machine Intelligence, 1998;20(8): 832-844.

5.2.1.12. Other Algorithms

The pattern classification and statistical techniques described aboveare merely examples of the types of models that can be used to constructa model for classification. Moreover, combinations of the techniquesdescribed above can be used. Some combinations, such as the use of thecombination of decision trees and boosting, have been described.However, many other combinations are possible. In addition, in othertechniques in the art such as Projection Pursuit and Weighted Voting canbe used to construct a progression classifier.

5.2.2. Methods of Determining Aberrant Regulation of CML Target Genes

The invention also provides methods and compositions for determiningaberrant regulation in CML target genes and/or their encoded proteins.Such information can be used to determine a treatment regimen for apatient. For example, patients who have a defective regulation of a CMLtarget gene can be identified. A treatment regimen including a therapyto regulate the gene can be prescribed to the patient. Thus, theinvention provides methods and composition for assigning treatmentregimen for a cancer patient. The invention also provides methods andcomposition for monitoring treatment progress for a CML patient based onthe status of one or more of the CML target proteins.

A variety of methods can be employed for the diagnostic and prognosticevaluation of patients for their status of CML target genes or proteins.In one embodiment, measurements of expression level of one or more ofthe CML target genes listed in Tables 5a and 5b, and/or abundance oractivity level the encoded proteins are used. One or more of these genesor proteins having a level of expression or activity deviated from arespective predetermined threshold indicate aberrant regulation of thegenes or proteins.

In one embodiment, the method comprises determining an expression levelof a CML target gene (a gene listed in Table 5a or 5b) in the sample ofa patient, and determining whether the expression level is deviated(above or below) a predetermined threshold, and the expression leveldeviated from a predetermined threshold level indicates aberrantregulation of the gene in the patient. Preferably, the predeterminedthreshold level is at least 2-fold, 4-fold, 8-fold, or 10-fold of thenormal expression level of an aberrantly up-regulated CML target gene orless than 50%, 25%, 10% or 1% of the normal level of an aberrantlydown-regulated CML target gene. In another embodiment, the methodcomprises determining a level of abundance of a CML target protein,i.e., a protein encoded by a CML target gene, in a sample from apatient, and determining whether the level of abundance is deviated apredetermined threshold, and a level of abundance of the proteindeviated from a predetermined threshold level indicates aberrantregulation of the protein in the patient. In still another embodiment,the method comprises determining a level of activity of a proteinencoded by the CML target gene in a sample of a patient, and determiningwhether the level of activity is deviated a predetermined threshold, andan activity level deviated from a predetermined threshold levelindicates aberrant regulation of the protein in the patient. A reducedactivity may be a result of mutation of the CML target gene. Thus, theinvention also provides a method for evaluating the status of CML targetin a patient, comprising determining a mutation in a CML target gene ora protein encoded by the CML target gene in a sample from the patient,and the detection of a mutation causing the activity of the CML targetprotein to deviate from a predetermined threshold level indicatesaberrant regulation of the protein in the patient. Preferably, thepredetermined threshold level of abundance or activity is at least2-fold, 4-fold, 8-fold, or 10-fold above the normal level of abundanceor activity of an aberrantly up-regulated CML target protein or lessthan 50%, 25%, 10% or 1% of the normal level of an aberrantlydown-regulated CML target protein. In the foregoing embodiments, and theembodiments described below, the sample can be an ex vivo cell sample,e.g., cells in a cell culture, or in vivo cells.

In a specific embodiment, the method comprises determining an expressionlevel of a CML target gene selected from the group consisting of theup-regulated genes listed in Table 3 (which is a subset of the geneslisted in Table 5a) in the sample of a patient, and determining whetherthe expression level is above a predetermined threshold, and anexpression level above a predetermined threshold level indicatesaberrant regulation of the gene in the patient. Preferably, thepredetermined threshold level is at least 2-fold, 4-fold, 8-fold, or10-fold of the normal expression level of the gene. In anotherembodiment, the method comprises determining a level of abundance of aprotein encoded by a gene selected from the group consisting of theup-regulated genes listed in Table 3 in a sample from a patient, anddetermining whether the level is above a predetermined threshold, and alevel of abundance of the protein above a predetermined threshold levelindicates aberrant regulation of the protein in the patient.

In another specific embodiment, the method comprises determining anexpression level of a CML target gene selected from the group consistingof the down-regulated genes listed in Table 3 in the sample of apatient, and determining whether the expression level is below apredetermined threshold, and an expression level below a predeterminedthreshold level indicates aberrant regulation of the gene in thepatient. Preferably, the predetermined threshold level is a level lessthan 50%, 25%, 10% or 1% of the normal expression level of the gene. Inanother embodiment, the method comprises determining a level ofabundance of a protein encoded by a gene selected from the groupconsisting of the down-regulated genes listed in Table 3 in a samplefrom a patient, and determining whether the level is below apredetermined threshold, and a level of abundance of the protein below apredetermined threshold level indicates aberrant regulation of theprotein in the patient.

In one embodiment, the method comprises determining an expression levelof an imatinib resistance gene (a gene listed in Table 4) in the sampleof a patient, and determining whether the expression level is deviated(above or below) a predetermined threshold, and an expression leveldeviated from a predetermined threshold level indicates that the patientis resistant to imatinib treatment. Preferably, the predeterminedthreshold level is at least 2-fold, 4-fold, 8-fold, or 10-fold of thenormal expression level of an aberrantly up-regulated imatinibresistance gene or less than 50%, 25%, 10% or 1% of the normal level ofan aberrantly down-regulated imatinib resistance gene. In anotherembodiment, the method comprises determining a level of abundance of animatinib resistance protein, i.e., a protein encoded by an imatinibresistance gene, in a sample from a patient, and determining whether thelevel is deviated (above or below) a predetermined threshold, and alevel of abundance of the protein deviated from a predeterminedthreshold level indicates that the patient is resistant to imatinibtreatment. In still another embodiment, the method comprises determininga level of activity of a protein encoded by an imatinib resistance genein a sample of a patient, and determining whether the level is deviated(above or below) a predetermined threshold, and an activity leveldeviated from a predetermined threshold level indicates that the patientis resistant to imatinib treatment. Such reduce activity may be a resultof mutation of the imatinib resistance gene. Thus, the invention alsoprovides a method for evaluating imatinib resistance in a patient,comprising determining a mutation in an imatinib resistance gene or aprotein encoded by the imatinib resistance gene in a sample from thepatient, and the detection of a mutation causing the activity of theimatinib resistance protein to deviate from a predetermined thresholdlevel indicates the patient is resistant to imatinib treatment.Preferably, the predetermined threshold level of abundance or activityis at least 2-fold, 4-fold, 8-fold, or 10-fold above the normal level ofabundance or activity of an aberrantly up-regulated imatinib resistanceprotein or less than 50%, 25%, 10% or 1% of the normal level of anaberrantly down-regulated imatinib resistance protein.

In a specific embodiment, imatinib resistance is determined according tothe expression levels of one or more genes selected from the groupconsisting of serine threonine kinases CTRL, MAP21K14, CLK3, MAP kinaseMKNK2, the tyrosine kinase oncogene FYN, TCF7 (a putatively T cellspecific transcription factor), guanine nucleotide binding proteins GNAZand GNG11, and the MAF.

Such methods may, for example, utilize reagents such as nucleotidesequences and antibodies, e.g., the CML progression nucleotidesequences, and antibodies directed against CML progression proteins,including peptide fragments thereof. Specifically, such reagents may beused, for example, for: (1) the detection of the presence of mutationsin a CML progression gene, or the detection of either over- orunder-expression of a CML progression gene relative to the normalexpression level; and (2) the detection of either an over- or anunder-abundance of a CML progression protein relative to the normal CMLprogression protein level. These methods are also applicable to imatinibresistance genes and/or proteins.

The methods described herein may be performed, for example, by utilizingpre-packaged diagnostic kits comprising nucleic acid of at least onespecific CML progression gene or an antibody that binds a CMLprogression/target protein or an IM resistance protein described herein,which may be conveniently used, e.g., in clinical settings, to diagnosepatients exhibiting CML progression/target protein related disorder orabnormalities or exhibiting IM resistance.

For the detection of mutations in a CML progression/target gene or an IMresistance gene, any nucleated cell can be used as a starting source forgenomic nucleic acid, e.g., bone marrow or peripheral blood. For thedetection of expression of a CML progression/target gene or an IMresistance gene or CML progression/target gene or IM resistance geneproducts, any cell type or tissue in which the CML progression/targetgene or the IM resistance gene is expressed may be utilized.

Nucleic acid-based detection techniques and peptide detection techniquesare described in Section 5.3., infra. In one embodiment, the expressionlevels of one or more marker genes are measured using qRT-PCR.

5.2.3. Methods of Detecting CML Cells

The invention also provides diagnostic methods for the detection of CMLcells, e.g., advanced phase CML hematopoetic stem cells and/or immaturemyeloid cells, by detecting a cell surface expressed CML progressionprotein (e.g., PRAME or CD47) or conserved variants or peptide fragmentsthereof, using, for example, immunoassays wherein the CML progressionprotein or conserved variants or peptide fragments are detected by theirinteraction with an anti-CML progression protein antibody.

For example, antibodies, or fragments of antibodies, such as thosedescribed in the present invention may be used to quantitatively orqualitatively detect advanced phase CML hematopoetic stem cells and/orimmature myeloid cells by the presence of a CML progression protein orconserved variants or peptide fragments thereof on their surfaces. Thiscan be accomplished, for example, by immunofluorescence techniquesemploying a fluorescently labeled antibody (see below, this Section)coupled with light microscopic, flow cytometric, or fluorimetricdetection.

The antibodies (or fragments thereof) useful in the present inventionmay, additionally, be employed histologically, as in immunofluorescenceor immunoelectron microscopy, for in situ detection of a CML progressionprotein or conserved variants or peptide fragments thereof. In situdetection may be accomplished by removing a histological specimen from apatient, e.g., bone marrow, and applying thereto a labeled antibody ofthe present invention. The antibody (or fragment) is preferably appliedby overlaying the labeled antibody (or fragment) onto a biologicalsample. Through the use of such a procedure, it is possible to determinenot only the presence of the CML progression protein, or conservedvariants or peptide fragments, but also its distribution in the examinedtissue. Using the present invention, those of ordinary skill willreadily perceive that any of a wide variety of histological methods(such as staining procedures) can be modified in order to achieve suchin situ detection.

Immunoassays for a CML progression protein or conserved variants orpeptide fragments thereof will typically comprise incubating a sample,such as a biological fluid, a tissue extract, freshly harvested cells,or lysates of cells which have been incubated in cell culture, in thepresence of a detectably labeled antibody capable of identifying A CMLprogression protein or conserved variants or peptide fragments thereof,and detecting the bound antibody by any of a number of techniqueswell-known in the art.

The biological sample may be brought in contact with and immobilizedonto a solid phase support or carrier such as nitrocellulose, or othersolid support which is capable of immobilizing cells, cell particles orsoluble proteins. The support may then be washed with suitable buffersfollowed by treatment with the detectably labeled antibody specific fora CML progression protein. The solid phase support may then be washedwith the buffer a second time to remove unbound antibody. The amount ofbound label on solid support may then be detected by conventional means.

By “solid phase support or carrier” is intended any support capable ofbinding an antigen or an antibody. Well-known supports or carriersinclude glass, polystyrene, polypropylene, polyethylene, dextran, nylon,amylases, natural and modified celluloses, polyacrylamides, gabbros, andmagnetite. The nature of the carrier can be either soluble to someextent or insoluble for the purposes of the present invention. Thesupport material may have virtually any possible structuralconfiguration so long as the coupled molecule is capable of binding toan antigen or antibody. Thus, the support configuration may bespherical, as in a bead, or cylindrical, as in the inside surface of atest tub, or the external surface of a rod. Alternatively, the surfacemay be flat such as a sheet, test strip, etc. Preferred supports includepolystyrene beads. Those skilled in the art will know many othersuitable carriers for binding antibody or antigen, or will be able toascertain the same by use of routine experimentation.

The binding activity of a given lot of an antibody may be determinedaccording to well-known methods. Those skilled in the art will be ableto determine operative and optimal assay conditions for eachdetermination by employing routine experimentation.

One of the ways in which the antibody specific to a CML progressionprotein can be detectably labeled is by linking the same to an enzymeand use in an enzyme immunoassay (EIA) (Voller, A., “The Enzyme LinkedImmunosorbent Assay (ELISA)”, 1978, Diagnostic Horizons 2:1-7,Microbiological Associates Quarterly Publication, Walkersville, Md.);Voller, A. et al., 1978, J. Clin. Pathol. 31:507-520; Butler, J. E.,1981, Meth. Enzymol. 73:482-523; Maggio, E. (ed.), 1980, EnzymeImmunoassay, CRC Press, Boca Raton, Fla.,; Ishikawa, E. et al., (eds.),1981, Enzyme Immunoassay, Kgaku Shoin, Tokyo). The enzyme which is boundto the antibody will react with an appropriate substrate, preferably achromogenic substrate, in such a manner as to produce a chemical moietywhich can be detected, for example, by spectrophotometric, fluorimetricor by visual means. Enzymes which can be used to detectably label theantibody include, but are not limited to, malate dehydrogenase,staphylococcal nuclease, delta-5-steroid isomerase, yeast alcoholdehydrogenase, alpha-glycerophosphate, dehydrogenase, triose phosphateisomerase, horseradish peroxidase, alkaline phosphatase, asparaginase,glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase,glucose-6-phosphate dehydrogenase, glucoamylase andacetylcholinesterase. The detection can be accomplished by colorimetricmethods which employ a chromogenic substrate for the enzyme. Detectionmay also be accomplished by visual comparison of the extent of enzymaticreaction of a substrate in comparison with similarly prepared standards.

Detection may also be accomplished using any of a variety of otherimmunoassays. For example, by radioactively labeling the antibodies orantibody fragments, it is possible to detect a CML progression proteinthrough the use of a radioimmunoassay (RIA) (see, for example,Weintraub, B., Principles of Radioimmunoassays, Seventh Training Courseon Radioligand Assay Techniques, The Endocrine Society, March, 1986,which is incorporated by reference herein). The radioactive isotope canbe detected by such means as the use of a gamma counter or ascintillation counter or by autoradiography.

It is also possible to label the antibody with a fluorescent compound.When the fluorescently labeled antibody is exposed to light of theproper wave length, its presence can then be detected due tofluorescence. Among the most commonly used fluorescent labelingcompounds are fluorescein isothiocyanate, rhodamine, phycoerythrin,phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine.

The antibody can also be detectably labeled using fluorescence emittingmetals such as ¹⁵²Eu, or others of the lanthanide series. These metalscan be attached to the antibody using such metal chelating groups asdiethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraaceticacid (EDTA).

The antibody also can be detectably labeled by coupling it to achemiluminescent compound. The presence of the chemiluminescent-taggedantibody is then determined by detecting the presence of luminescencethat arises during the course of a chemical reaction. Examples ofparticularly useful chemiluminescent labeling compounds are luminol,isoluminol, theromatic acridinium ester, imidazole, acridinium salt andoxalate ester.

Likewise, a bioluminescent compound may be used to label the antibody ofthe present invention. Bioluminescence is a type of chemiluminescencefound in biological systems in, which a catalytic protein increases theefficiency of the chemiluminescent reaction. The presence of abioluminescent protein is determined by detecting the presence ofluminescence. Important bioluminescent compounds for purposes oflabeling are luciferin, luciferase and aequorin.

An antibody that is specific to a CML progression protein conjugated todetectable substances can be utilized to sort advanced phase CML cellsfrom normal cells by methods known to those of skill in the art. In oneembodiment, the advanced phase CML cells are sorted using a fluorescenceactivated cell sorter (FACS). Fluorescence activated cell sorting (FACS)is a well-known method for separating particles, including cells, basedon the fluorescent properties of the particles (Kamarch, 1987, MethodsEnzymol, 151:150-165). Laser excitation of fluorescent moieties in theindividual particles results in a small electrical charge allowingelectromagnetic separation of positive and negative particles from amixture.

In one embodiment, cells, e.g, cells in bone marrow or peripheral blood,obtained from a patient, e.g., a human, are incubated with fluorescentlylabeled antibody specific for the CML progression protein for a timesufficient to allow the labeled antibodies to bind to the cells. In analternative embodiment, such cells are incubated with the antibody, thecells are washed, and the cells are incubated with a second labeledantibody that recognizes the CML progression protein-specific antibody.In accordance with these embodiments, the cells are washed and processedthrough the cell sorter, allowing separation of cells that bind bothantibodies to be separated from hybrid cells that do not bind bothantibodies. FACS sorted particles may be directly deposited intoindividual wells of 96-well or 384-well plates to facilitate separationand further characterization.

5.2.4. Sample Collection

In the present invention, gene products, such as target polynucleotidemolecules or proteins, are extracted from a sample taken from a CMLpatient. The sample may be collected in any clinically acceptablemanner, but must be collected such that marker-derived polynucleotides(i.e., RNA) are preserved (if gene expression is to be measured) orproteins are preserved (if encoded proteins are to be measured). In oneembodiment, bone marrow samples are used. In another embodiment,peripheral blood samples are used. In one embodiment, the pre-treatmentbone marrow or peripheral blood sample from a patient is used. Inanother embodiment, the treatment bone marrow or peripheral blood samplefrom a patient after and/or during treatment is used. In one embodiment,the unsorted bone marrow or peripheral blood sample from a patient isused. In one embodiment, the unsorted bone marrow or peripheral bloodsample from a clinical chronic phase patient is used. In anotherembodiment, the sorted bone marrow or peripheral blood sample from apatient after and/or during treatment is used. Other suitable samplesmay comprise any clinically relevant tissue sample, such as a tumorbiopsy or fine needle aspirate, or a sample of body fluid, such asblood, plasma, serum, lymph, ascitic fluid, cystic fluid, or urine. Thesample may be taken from a human, or, in a veterinary context, fromnon-human animals such as ruminants, horses, swine or sheep, or fromdomestic companion animals such as felines and canines.

In a specific embodiment, mRNA or nucleic acids derived therefrom (i.e.,cDNA or amplified RNA or amplified DNA) are preferably labeleddistinguishably from polynucleotide molecules of a reference sample, andboth are simultaneously or independently hybridized to a microarraycomprising some or all of the markers or marker sets or subsetsdescribed above. Alternatively, mRNA or nucleic acids derived therefrommay be labeled with the same label as the reference polynucleotidemolecules, wherein the intensity of hybridization of each at aparticular probe is compared.

Methods for preparing total and poly(A)+ RNA are well known and aredescribed generally in Sambrook et al., MOLECULAR CLONING—A LABORATORYMANUAL (2ND ED.), Vols. 1-3, Cold Spring Harbor Laboratory, Cold SpringHarbor, N.Y. (1989)) and Ausubel et al., CURRENT PROTOCOLS IN MOLECULARBIOLOGY, vol. 2, Current Protocols Publishing, New York (1994)).Preferably, total RNA, or total mRNA (poly(A)+ RNA) is measured in themethods of the invention directly or indirectly (e.g., via measuringcDNA or cRNA).

RNA may be isolated from eukaryotic cells by procedures that involvelysis of the cells and denaturation of the proteins contained therein.Cells of interest include wild-type cells (i.e., non-cancerous),drug-exposed wild-type cells, tumor- or tumor-derived cells, modifiedcells, normal or tumor cell line cells, and drug-exposed modified cells.Preferably, the cells are breast cancer tumor cells.

Additional steps may be employed to remove DNA. Cell lysis may beaccomplished with a nonionic detergent, followed by microcentrifugationto remove the nuclei and hence the bulk of the cellular DNA. In oneembodiment, RNA is extracted from cells of the various types of interestusing guanidinium thiocyanate lysis followed by CsCl centrifugation toseparate the RNA from DNA (Chirgwin et al., Biochemistry 18:5294-5299(1979)). Poly(A)+ RNA is selected by selection with oligo-dT cellulose(see Sambrook et al., MOLECULAR CLONING—A LABORATORY MANUAL (2ND ED.),Vols. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.(1989). Alternatively, separation of RNA from DNA can be accomplished byorganic extraction, for example, with hot phenol orphenol/chloroform/isoamyl alcohol.

If desired, RNase inhibitors may be added to the lysis buffer. Likewise,for certain cell types, it may be desirable to add a proteindenaturation/digestion step to the protocol.

For many applications, it is desirable to preferentially enrich mRNAwith respect to other cellular RNAs, such as transfer RNA (tRNA) andribosomal RNA (rRNA). Most mRNAs contain a poly(A) tail at their 3′ end.This allows them to be enriched by affinity chromatography, for example,using oligo(dT) or poly(U) coupled to a solid support, such as celluloseor Sephadex™ (see Ausubel et al., CURRENT PROTOCOLS IN MOLECULARBIOLOGY, vol. 2, Current Protocols Publishing, New York (1994). Oncebound, poly(A)+ mRNA is eluted from the affinity column using 2 mMEDTA/0.1% SDS.

In a specific embodiment, total RNA or total mRNA from cells is used inthe methods of the invention. The source of the RNA can be cells of ananimal, e.g., human, mammal, primate, non-human animal, dog, cat, mouse,rat, bird, etc. In specific embodiments, the method of the invention isused with a sample containing total mRNA or total RNA from 1×10⁶ cellsor less. In another embodiment, proteins can be isolated from theforegoing sources, by methods known in the art, for use in expressionanalysis at the protein level.

Probes to the homologs of the marker sequences disclosed herein can beemployed preferably when non-human nucleic acid is being assayed.

5.2.5. Determination of Abundance Levels of Gene Products

The abundance levels of the gene products of the genes in a sample maybe determined by any means known in the art. The levels may bedetermined by isolating and determining the level (i.e., amount) ofnucleic acid transcribed from each marker gene. Alternatively, oradditionally, the level of specific proteins encoded by a marker genemay be determined

The levels of transcripts of specific marker genes can be accomplishedby determining the amount of mRNA, or polynucleotides derived therefrom,present in a sample. Any method for determining RNA levels can be used.For example, RNA is isolated from a sample and separated on an agarosegel. The separated RNA is then transferred to a solid support, such as afilter. Nucleic acid probes representing one or more markers are thenhybridized to the filter by northern hybridization, and the amount ofmarker-derived RNA is determined. Such determination can be visual, ormachine-aided, for example, by use of a densitometer. Another method ofdetermining RNA levels is by use of a dot-blot or a slot-blot. In thismethod, RNA, or nucleic acid derived therefrom, from a sample islabeled. The RNA or nucleic acid derived therefrom is then hybridized toa filter containing oligonucleotides derived from one or more markergenes, wherein the oligonucleotides are placed upon the filter atdiscrete, easily-identifiable locations. Hybridization, or lack thereof,of the labeled RNA to the filter-bound oligonucleotides is determinedvisually or by densitometer. Polynucleotides can be labeled using aradiolabel or a fluorescent (i.e., visible) label.

The levels of transcripts of particular marker genes may also beassessed by determining the level of the specific protein expressed fromthe marker genes. This can be accomplished, for example, by separationof proteins from a sample on a polyacrylamide gel, followed byidentification of specific marker-derived proteins using antibodies in awestern blot. Alternatively, proteins can be separated bytwo-dimensional gel electrophoresis systems. Two-dimensional gelelectrophoresis is well-known in the art and typically involvesisoelectric focusing along a first dimension followed by SDS-PAGEelectrophoresis along a second dimension. See, e.g., Hames et al, 1990,GEL ELECTROPHORESIS OF PROTEINS: A PRACTICAL APPROACH, IRL Press, NewYork; Shevchenko et al., Proc. Nat'l Acad. Sci. USA 93:1440-1445 (1996);Sagliocco et al., Yeast 12:1519-1533 (1996); Lander, Science 274:536-539(1996). The resulting electropherograms can be analyzed by numeroustechniques, including mass spectrometric techniques, western blottingand immunoblot analysis using polyclonal and monoclonal antibodies.

Alternatively, marker-derived protein levels can be determined byconstructing an antibody microarray in which binding sites compriseimmobilized, preferably monoclonal, antibodies specific to a pluralityof protein species encoded by the cell genome. Preferably, antibodiesare present for a substantial fraction of the marker-derived proteins ofinterest. Methods for making monoclonal antibodies are well known (see,e.g., Harlow and Lane, 1988, ANTIBODIES: A LABORATORY MANUAL, ColdSpring Harbor, N.Y., which is incorporated in its entirety for allpurposes). In one embodiment, monoclonal antibodies are raised againstsynthetic peptide fragments designed based on genomic sequence of thecell. With such an antibody array, proteins from the cell are contactedto the array, and their binding is assayed with assays known in the art.Generally, the expression, and the level of expression, of proteins ofdiagnostic or prognostic interest can be detected throughimmunohistochemical staining of tissue slices or sections.

Finally, levels of transcripts of marker genes in a number of tissuespecimens may be characterized using a “tissue array” (Kononen et al.,Nat. Med. 4(7):844-7 (1998)). In a tissue array, multiple tissue samplesare assessed on the same microarray. The arrays allow in situ detectionof RNA and protein levels; consecutive sections allow the analysis ofmultiple samples simultaneously.

5.2.5.1. Microarrays

In preferred embodiments, polynucleotide microarrays are used to measureexpression so that the expression status of each of the markers above isassessed simultaneously. Generally, microarrays according to theinvention comprise a plurality of markers informative for clinicalcategory determination, for a particular disease or condition.

The invention also provides a microarray comprising for each of aplurality of genes, said genes being all or at least 5, 10, 20, 30, 40,50, 70, 100 or 200 of the genes listed in Tables 1a and/or 1b or any ofTables 2a-2b, 4 and 5a-5b, or all or at least 5, 10, or 15 of the geneslisted in Table 3, one or more polynucleotide probes complementary andhybridizable to a sequence in said gene, wherein polynucleotide probescomplementary and hybridizable to said genes constitute at least 50%,60%, 70%, 80%, 90%, 95%, or 98% of the probes on said microarray. In aparticular embodiment, the invention provides such a microarray whereinthe plurality of genes comprises the 20 genes listed in Table 3 or the228 genes listed in Table 4 or the 368 genes listed in Tables 5a and 5b.The microarray can be in a sealed container.

The microarrays preferably comprise at least 2, 3, 4, 5, 7, 10, 15, 20,25, 30, 35, 40, 45, 50, 75, 100, 150, 200 or more of markers, or all ofthe markers, or any combination of markers, identified as informativefor CML progression and/or imatinib resistance, e.g., within Tables 1aand 1b or any of Tables 2a-2b, 3, 4, and 5a-5b. The actual number ofinformative markers the microarray comprises will vary depending uponthe particular condition of interest.

In other embodiments, the invention provides polynucleotide arrays inwhich the CML progression markers comprise at least 50%, 60%, 70%, 80%,85%, 90%, 95% or 98% of the probes on the array. In another specificembodiment, the microarray comprises a plurality of probes, wherein saidplurality of probes comprise probes complementary and hybridizable to atleast 75% of the CML progression markers.

General methods pertaining to the construction of microarrays comprisingthe marker sets and/or subsets above are described in the followingsections.

5.2.5.2. Construction of Microarrays

Microarrays are prepared by selecting probes which comprise apolynucleotide sequence, and then immobilizing such probes to a solidsupport or surface. For example, the probes may comprise DNA sequences,RNA sequences, or copolymer sequences of DNA and RNA. The polynucleotidesequences of the probes may also comprise DNA and/or RNA analogues, orcombinations thereof. For example, the polynucleotide sequences of theprobes may be full or partial fragments of genomic DNA. Thepolynucleotide sequences of the probes may also be synthesizednucleotide sequences, such as synthetic oligonucleotide sequences. Theprobe sequences can be synthesized either enzymatically in vivo,enzymatically in vitro (e.g., by PCR), or non-enzymatically in vitro.

The probe or probes used in the methods of the invention are preferablyimmobilized to a solid support which may be either porous or non-porous.For example, the probes may be polynucleotide sequences which areattached to a nitrocellulose or nylon membrane or filter covalently ateither the 3′ or the 5′ end of the polynucleotide. Such hybridizationprobes are well known in the art (see, e.g., Sambrook et al., MOLECULARCLONING—A LABORATORY MANUAL (2ND ED.), Vols. 1-3, Cold Spring HarborLaboratory, Cold Spring Harbor, N.Y. (1989). Alternatively, the solidsupport or surface may be a glass or plastic surface. In a particularlypreferred embodiment, hybridization levels are measured to microarraysof probes consisting of a solid phase on the surface of which areimmobilized a population of polynucleotides, such as a population of DNAor DNA mimics, or, alternatively, a population of RNA or RNA mimics. Thesolid phase may be a nonporous or, optionally, a porous material such asa gel.

In preferred embodiments, a microarray comprises a support or surfacewith an ordered array of binding (e.g., hybridization) sites or “probes”each representing one of the markers described herein. Preferably themicroarrays are addressable arrays, and more preferably positionallyaddressable arrays. More specifically, each probe of the array ispreferably located at a known, predetermined position on the solidsupport such that the identity (i.e., the sequence) of each probe can bedetermined from its position in the array (i.e., on the support orsurface). In preferred embodiments, each probe is covalently attached tothe solid support at a single site.

Microarrays can be made in a number of ways, of which several aredescribed below. However produced, microarrays share certaincharacteristics. The arrays are reproducible, allowing multiple copiesof a given array to be produced and easily compared with each other.Preferably, microarrays are made from materials that are stable underbinding (e.g., nucleic acid hybridization) conditions. The microarraysare preferably small, e.g., between 1 cm² and 25 cm², between 12 cm² and13 cm², or 3 cm². However, larger arrays are also contemplated and maybe preferable, e.g., for use in screening arrays. Preferably, a givenbinding site or unique set of binding sites in the microarray willspecifically bind (e.g., hybridize) to the product of a single gene in acell (e.g., to a specific mRNA, or to a specific cDNA derivedtherefrom). However, in general, other related or similar sequences willcross hybridize to a given binding site.

The microarrays of the present invention include one or more testprobes, each of which has a polynucleotide sequence that iscomplementary to a subsequence of RNA or DNA to be detected. Preferably,the position of each probe on the solid surface is known. Indeed, themicroarrays are preferably positionally addressable arrays.Specifically, each probe of the array is preferably located at a known,predetermined position on the solid support such that the identity(i.e., the sequence) of each probe can be determined from its positionon the array (i.e., on the support or surface).

According to the invention, the microarray is an array (i.e., a matrix)in which each position represents one of the markers described herein.For example, each position can contain a DNA or DNA analogue based ongenomic DNA to which a particular RNA or cDNA transcribed from thatgenetic marker can specifically hybridize. The DNA or DNA analogue canbe, e.g., a synthetic oligomer or a gene fragment. In one embodiment,probes representing each of the markers are present on the array. In apreferred embodiment, the array comprises probes for each of the markerslisted in Tables 1a and/or 1b or any one of Tables 2a-2b, 3, 4, and5a-5b.

5.2.5.3. Preparing Probes for Microarrays

As noted above, the “probe” to which a particular polynucleotidemolecule specifically hybridizes according to the invention contains acomplementary genomic polynucleotide sequence. The probes of themicroarray preferably consist of nucleotide sequences of no more than1,000 nucleotides. In some embodiments, the probes of the array consistof nucleotide sequences of 10 to 1,000 nucleotides. In a preferredembodiment, the nucleotide sequences of the probes are in the range of10-200 nucleotides in length and are genomic sequences of a species oforganism, such that a plurality of different probes is present, withsequences complementary and thus capable of hybridizing to the genome ofsuch a species of organism, sequentially tiled across all or a portionof such genome. In other specific embodiments, the probes are in therange of 10-30 nucleotides in length, in the range of 10-40 nucleotidesin length, in the range of 20-50 nucleotides in length, in the range of40-80 nucleotides in length, in the range of 50-150 nucleotides inlength, in the range of 80-120 nucleotides in length, and mostpreferably are 60 nucleotides in length.

The probes may comprise DNA or DNA “mimics” (e.g., derivatives andanalogues) corresponding to a portion of an organism's genome. Inanother embodiment, the probes of the microarray are complementary RNAor RNA mimics. DNA mimics are polymers composed of subunits capable ofspecific, Watson-Crick-like hybridization with DNA, or of specifichybridization with RNA. The nucleic acids can be modified at the basemoiety, at the sugar moiety, or at the phosphate backbone. Exemplary DNAmimics include, e.g., phosphorothioates.

DNA can be obtained, e.g., by polymerase chain reaction (PCR)amplification of genomic DNA or cloned sequences. PCR primers arepreferably chosen based on a known sequence of the genome that willresult in amplification of specific fragments of genomic DNA. Computerprograms that are well known in the art are useful in the design ofprimers with the required specificity and optimal amplificationproperties, such as Oligo version 5.0 (National Biosciences). Typicallyeach probe on the microarray will be between 10 bases and 50,000 bases,usually between 300 bases and 1,000 bases in length. PCR methods arewell known in the art, and are described, for example, in Innis et al.,eds., PCR PROTOCOLS: A GUIDE TO METHODS AND APPLICATIONS, Academic PressInc., San Diego, Calif. (1990). It will be apparent to one skilled inthe art that controlled robotic systems are useful for isolating andamplifying nucleic acids.

An alternative, preferred means for generating the polynucleotide probesof the microarray is by synthesis of synthetic polynucleotides oroligonucleotides, e.g., using N-phosphonate or phosphoramiditechemistries (Froehler et al., Nucleic Acid Res. 14:5399-5407 (1986);McBride et al., Tetrahedron Lett. 24:246-248 (1983)). Syntheticsequences are typically between about 10 and about 500 bases in length,more typically between about 20 and about 100 bases, and most preferablybetween about 40 and about 70 bases in length. In some embodiments,synthetic nucleic acids include non-natural bases, such as, but by nomeans limited to, inosine. As noted above, nucleic acid analogues may beused as binding sites for hybridization. An example of a suitablenucleic acid analogue is peptide nucleic acid (see, e.g., Egholm et al.,Nature 363:566-568 (1993); U.S. Pat. No. 5,539,083).

Probes are preferably selected using an algorithm that takes intoaccount binding energies, base composition, sequence complexity,cross-hybridization binding energies, and secondary structure. SeeFriend et al., International Patent Publication WO 01/05935, publishedJan. 25, 2001; Hughes et al., Nat. Biotech. 19:342-7 (2001).

A skilled artisan will also appreciate that positive control probes,e.g., probes known to be complementary and hybridizable to sequences inthe target polynucleotide molecules, and negative control probes, e.g.,probes known to not be complementary and hybridizable to sequences inthe target polynucleotide molecules, should be included on the array. Inone embodiment, positive controls are synthesized along the perimeter ofthe array. In another embodiment, positive controls are synthesized indiagonal stripes across the array. In still another embodiment, thereverse complement for each probe is synthesized next to the position ofthe probe to serve as a negative control. In yet another embodiment,sequences from other species of organism are used as negative controlsor as “spike-in” controls.

5.2.5.4. Attaching Probes to the Solid Surface

The probes are attached to a solid support or surface, which may bemade, e.g., from glass, plastic (e.g., polypropylene, nylon),polyacrylamide, nitrocellulose, gel, or other porous or nonporousmaterial. A preferred method for attaching the nucleic acids to asurface is by printing on glass plates, as is described generally bySchena et al, Science 270:467-470 (1995). This method is especiallyuseful for preparing microarrays of cDNA (See also, DeRisi et al, NatureGenetics 14:457-460 (1996); Shalon et al., Genome Res. 6:639-645 (1996);and Schena et al., Proc. Natl. Acad. Sci. U.S.A. 93:10539-11286 (1995)).

A second preferred method for making microarrays is by makinghigh-density oligonucleotide arrays. Techniques are known for producingarrays containing thousands of oligonucleotides complementary to definedsequences, at defined locations on a surface using photolithographictechniques for synthesis in situ (see, Fodor et al., 1991, Science251:767-773; Pease et al., 1994, Proc. Natl. Acad. Sci. U.S.A.91:5022-5026; Lockhart et al., 1996, Nature Biotechnology 14:1675; U.S.Pat. Nos. 5,578,832; 5,556,752; and 5,510,270) or other methods forrapid synthesis and deposition of defined oligonucleotides (Blanchard etal., Biosensors & Bioelectronics 11:687-690). When these methods areused, oligonucleotides (e.g., 60-mers) of known sequence are synthesizeddirectly on a surface such as a derivatized glass slide. Usually, thearray produced is redundant, with several oligonucleotide molecules perRNA.

Other methods for making microarrays, e.g., by masking (Maskos andSouthern, 1992, Nuc. Acids. Res. 20:1679-1684), may also be used. Inprinciple, and as noted supra, any type of array, for example, dot blotson a nylon hybridization membrane (see Sambrook et al., MOLECULARCLONING—A LABORATORY MANUAL (2ND ED.), Vols. 1-3, Cold Spring HarborLaboratory, Cold Spring Harbor, N.Y. (1989)) could be used. However, aswill be recognized by those skilled in the art, very small arrays willfrequently be preferred because hybridization volumes will be smaller.

In one embodiment, the arrays of the present invention are prepared bysynthesizing polynucleotide probes on a support. In such an embodiment,polynucleotide probes are attached to the support covalently at eitherthe 3′ or the 5′ end of the polynucleotide.

In a particularly preferred embodiment, microarrays are manufactured bymeans of an ink jet printing device for oligonucleotide synthesis, e.g.,using the methods and systems described by Blanchard in U.S. Pat. No.6,028,189; Blanchard et al., 1996, Biosensors and Bioelectronics11:687-690; Blanchard, 1998, in Synthetic DNA Arrays in GeneticEngineering, Vol. 20, J. K. Setlow, Ed., Plenum Press, New York at pages111-123. Specifically, the oligonucleotide probes in such microarraysare preferably synthesized in arrays, e.g., on a glass slide, byserially depositing individual nucleotide bases in “microdroplets” of ahigh surface tension solvent such as propylene carbonate. Themicrodroplets have small volumes (e.g., 100 pL or less, more preferably50 pL or less) and are separated from each other on the microarray(e.g., by hydrophobic domains) to form circular surface tension wellswhich define the locations of the array elements (i.e., the differentprobes). Microarrays manufactured by this ink-jet method are typicallyof high density, preferably having a density of at least about 2,500different probes per 1 cm². The polynucleotide probes are attached tothe support covalently at either the 3′ or the 5′ end of thepolynucleotide.

5.2.5.5. Target Labeling and Hybridization to Microarrays

The polynucleotide molecules which may be analyzed by the presentinvention (the “target polynucleotide molecules”) may be from anyclinically relevant source, but are expressed RNA or a nucleic acidderived therefrom (e.g., cDNA or amplified RNA derived from cDNA thatincorporates an RNA polymerase promoter), including naturally occurringnucleic acid molecules, as well as synthetic nucleic acid molecules. Inone embodiment, the target polynucleotide molecules comprise RNA,including, but by no means limited to, total cellular RNA, poly(A)⁺messenger RNA (mRNA) or fraction thereof, cytoplasmic mRNA, or RNAtranscribed from cDNA (i.e., cRNA; see, e.g., Linsley & Schelter, U.S.patent application Ser. No. 09/411,074, filed Oct. 4, 1999, or U.S. Pat.Nos. 5,545,522, 5,891,636, or 5,716,785). Methods for preparing totaland poly(A)⁺ RNA are well known in the art, and are described generally,e.g., in Sambrook et al., MOLECULAR CLONING—A LABORATORY MANUAL (2NDED.), Vols. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.(1989). In one embodiment, RNA is extracted from cells of the varioustypes of interest in this invention using guanidinium thiocyanate lysisfollowed by CsCl centrifugation (Chirgwin et al., 1979, Biochemistry18:5294-5299). In another embodiment, total RNA is extracted using asilica gel-based column, commercially available examples of whichinclude RNeasy (Qiagen, Valencia, Calif.) and StrataPrep (Stratagene, LaJolla, Calif.). In an alternative embodiment, which is preferred for S.cerevisiae, RNA is extracted from cells using phenol and chloroform, asdescribed in Ausubel et al., eds., 1989, CURRENT PROTOCOLS IN MOLECULARBIOLOGY, Vol. III, Green Publishing Associates, Inc., John Wiley & Sons,Inc., New York, at pp. 13.12.1-13.12.5). Poly(A)⁺ RNA can be selected,e.g., by selection with oligo-dT cellulose or, alternatively, byoligo-dT primed reverse transcription of total cellular RNA. In oneembodiment, RNA can be fragmented by methods known in the art, e.g., byincubation with ZnCl₂, to generate fragments of RNA. In anotherembodiment, the polynucleotide molecules analyzed by the inventioncomprise cDNA, or PCR products of amplified RNA or cDNA.

In one embodiment, total RNA, mRNA, or nucleic acids derived therefrom,is isolated from a sample taken from a CML patient. Targetpolynucleotide molecules that are poorly expressed in particular cellsmay be enriched using normalization techniques (Bonaldo et al., 1996,Genome Res. 6:791-806).

As described above, the target polynucleotides are detectably labeled atone or more nucleotides. Any method known in the art may be used todetectably label the target polynucleotides. Preferably, this labelingincorporates the label uniformly along the length of the RNA, and morepreferably, the labeling is carried out at a high degree of efficiency.One embodiment for this labeling uses oligo-dT primed reversetranscription to incorporate the label; however, conventional methods ofthis method are biased toward generating 3′ end fragments. Thus, in apreferred embodiment, random primers (e.g., 9-mers) are used in reversetranscription to uniformly incorporate labeled nucleotides over the fulllength of the target polynucleotides. Alternatively, random primers maybe used in conjunction with PCR methods or T7 promoter-based in vitrotranscription methods in order to amplify the target polynucleotides.

In a preferred embodiment, the detectable label is a luminescent label.For example, fluorescent labels, bioluminescent labels, chemiluminescentlabels, and colorimetric labels may be used in the present invention. Ina highly preferred embodiment, the label is a fluorescent label, such asa fluorescein, a phosphor, a rhodamine, or a polymethine dye derivative.Examples of commercially available fluorescent labels include, forexample, fluorescent phosphoramidites such as FluorePrime (AmershamPharmacia, Piscataway, N.J.), Fluoredite (Millipore, Bedford, Mass.),FAM (ABI, Foster City, Calif.), and Cy3 or Cy5 (Amersham Pharmacia,Piscataway, N.J.). In another embodiment, the detectable label is aradiolabeled nucleotide.

In a further preferred embodiment, target polynucleotide molecules froma patient sample are labeled differentially from target polynucleotidemolecules of a reference sample. The reference can comprise targetpolynucleotide molecules from normal cell samples (i.e., cell sample,e.g., bone marrow or peripheral blood, from those not afflicted withCML) or from cell samples, e.g., bone marrow or peripheral blood, fromchronic phase CML patients.

Nucleic acid hybridization and wash conditions are chosen so that thetarget polynucleotide molecules specifically bind or specificallyhybridize to the complementary polynucleotide sequences of the array,preferably to a specific array site, wherein its complementary DNA islocated.

Arrays containing double-stranded probe DNA situated thereon arepreferably subjected to denaturing conditions to render the DNAsingle-stranded prior to contacting with the target polynucleotidemolecules. Arrays containing single-stranded probe DNA (e.g., syntheticoligodeoxyribonucleic acids) may need to be denatured prior tocontacting with the target polynucleotide molecules, e.g., to removehairpins or dimers which form due to self complementary sequences.

Optimal hybridization conditions will depend on the length (e.g.,oligomer versus polynucleotide greater than 200 bases) and type (e.g.,RNA, or DNA) of probe and target nucleic acids. One of skill in the artwill appreciate that as the oligonucleotides become shorter, it maybecome necessary to adjust their length to achieve a relatively uniformmelting temperature for satisfactory hybridization results. Generalparameters for specific (i.e., stringent) hybridization conditions fornucleic acids are described in Sambrook et al., MOLECULAR CLONING—ALABORATORY MANUAL (2ND ED.), Vols. 1-3, Cold Spring Harbor Laboratory,Cold Spring Harbor, N.Y. (1989), and in Ausubel et al., CURRENTPROTOCOLS IN MOLECULAR BIOLOGY, vol. 2, Current Protocols Publishing,New York (1994). Typical hybridization conditions for the cDNAmicroarrays of Schena et al. are hybridization in 5×SSC plus 0.2% SDS at65° C. for four hours, followed by washes at 25° C. in low stringencywash buffer (1×SSC plus 0.2% SDS), followed by 10 minutes at 25° C. inhigher stringency wash buffer (0.1×SSC plus 0.2% SDS) (Schena et al.,Proc. Natl. Acad. Sci. U.S.A. 93:10614 (1993)). Useful hybridizationconditions are also provided in, e.g., Tijessen, 1993, HYBRIDIZATIONWITH NUCLEIC ACID PROBES, Elsevier Science Publishers B. V.; and Kricka,1992, NONISOTOPIC DNA PROBE TECHNIQUES, Academic Press, San Diego,Calif.

Particularly preferred hybridization conditions include hybridization ata temperature at or near the mean melting temperature of the probes(e.g., within 51° C., more preferably within 21° C.) in 1 M NaCl, 50 mMMES buffer (pH 6.5), 0.5% sodium sarcosine and 30% formamide.

5.2.5.6. Signal Detection and Data Analysis

When fluorescently labeled gene products are used, the fluorescenceemissions at each site of a microarray may be, preferably, detected byscanning confocal laser microscopy. In one embodiment, a separate scan,using the appropriate excitation line, is carried out for each of thetwo fluorophores used. Alternatively, a laser may be used that allowssimultaneous specimen illumination at wavelengths specific to the twofluorophores and emissions from the two fluorophores can be analyzedsimultaneously (see Shalon et al., 1996, “A DNA microarray system foranalyzing complex DNA samples using two-color fluorescent probehybridization,” Genome Research 6:639-645, which is incorporated byreference in its entirety for all purposes). In a preferred embodiment,the arrays are scanned with a laser fluorescent scanner with a computercontrolled X-Y stage and a microscope objective. Sequential excitationof the two fluorophores is achieved with a multi-line, mixed gas laserand the emitted light is split by wavelength and detected with twophotomultiplier tubes. Fluorescence laser scanning devices are describedin Schena et al., Genome Res. 6:639-645 (1996), and in other referencescited herein. Alternatively, the fiber-optic bundle described byFerguson et al., Nature Biotech. 14:1681-1684 (1996), may be used tomonitor mRNA abundance levels at a large number of sites simultaneously.

5.2.5.7. Other Assays for Detecting and Quantifying RNA

In addition to microarrays such as those described above any techniqueknown to one of skill for detecting and measuring RNA can be used inaccordance with the methods of the invention. Non-limiting examples oftechniques include Northern blotting, nuclease protection assays, RNAfingerprinting, polymerase chain reaction, ligase chain reaction, Qbetareplicase, isothermal amplification method, strand displacementamplification, transcription based amplification systems, nucleaseprotection (SI nuclease or RNAse protection assays), SAGE as well asmethods disclosed in International Publication Nos. WO 88/10315 and WO89/06700, and International Applications Nos. PCT/US87/00880 andPCT/US89/01025.

A standard Northern blot assay can be used to ascertain an RNAtranscript size, identify alternatively spliced RNA transcripts, and therelative amounts of mRNA in a sample, in accordance with conventionalNorthern hybridization techniques known to those persons of ordinaryskill in the art. In Northern blots, RNA samples are first separated bysize via electrophoresis in an agarose gel under denaturing conditions.The RNA is then transferred to a membrane, crosslinked and hybridizedwith a labeled probe. Nonisotopic or high specific activity radiolabeledprobes can be used including random-primed, nick-translated, orPCR-generated DNA probes, in vitro transcribed RNA probes, andoligonucleotides. Additionally, sequences with only partial homology(e.g., cDNA from a different species or genomic DNA fragments that mightcontain an exon) may be used as probes. The labeled probe, e.g., aradiolabelled cDNA, either containing the full-length, single strandedDNA or a fragment of that DNA sequence may be at least 20, at least 30,at least 50, or at least 100 consecutive nucleotides in length. Theprobe can be labeled by any of the many different methods known to thoseskilled in this art. The labels most commonly employed for these studiesare radioactive elements, enzymes, chemicals that fluoresce when exposedto ultraviolet light, and others. A number of fluorescent materials areknown and can be utilized as labels. These include, but are not limitedto, fluorescein, rhodamine, auramine, Texas Red, AMCA blue and LuciferYellow. A particular detecting material is anti-rabbit antibody preparedin goats and conjugated with fluorescein through an isothiocyanate.Proteins can also be labeled with a radioactive element or with anenzyme. The radioactive label can be detected by any of the currentlyavailable counting procedures. Non-limiting examples of isotopes include³H, ¹⁴C, ³²P, ³⁵S, ³⁶Cl, ⁵¹Cr, ⁵⁷Co, ⁵⁸Co, ⁵⁹Fe, ⁹⁰Y, ¹²⁵I, ¹³¹I, and¹⁸⁶Re. Enzyme labels are likewise useful, and can be detected by any ofthe presently utilized colorimetric, spectrophotometric,fluorospectrophotometric, amperometric or gasometric techniques. Theenzyme is conjugated to the selected particle by reaction with bridgingmolecules such as carbodiimides, diisocyanates, glutaraldehyde and thelike. Any enzymes known to one of skill in the art can be utilized.Examples of such enzymes include, but are not limited to, peroxidase,beta-D-galactosidase, urease, glucose oxidase plus peroxidase andalkaline phosphatase. U.S. Pat. Nos. 3,654,090, 3,850,752, and 4,016,043are referred to by way of example for their disclosure of alternatelabeling material and methods.

Nuclease protection assays (including both ribonuclease protectionassays and S1 nuclease assays) can be used to detect and quantitatespecific mRNAs. In nuclease protection assays, an antisense probe(labeled with, e.g., radiolabeled or nonisotopic) hybridizes in solutionto an RNA sample. Following hybridization, single-stranded, unhybridizedprobe and RNA are degraded by nucleases. An acrylamide gel is used toseparate the remaining protected fragments. Typically, solutionhybridization is more efficient than membrane-based hybridization, andit can accommodate up to 100 μg of sample RNA, compared with the 20-30μg maximum of blot hybridizations.

The ribonuclease protection assay, which is the most common type ofnuclease protection assay, requires the use of RNA probes.Oligonucleotides and other single-stranded DNA probes can only be usedin assays containing S1 nuclease. The single-stranded, antisense probemust typically be completely homologous to target RNA to preventcleavage of the probe:target hybrid by nuclease.

Serial Analysis Gene Expression (SAGE), which is described in e.g.,Velculescu et al., 1995, Science 270:484-7; Carulli, et al., 1998,Journal of Cellular Biochemistry Supplements 30/31:286-96, can also beused to determine RNA abundances in a cell sample.

Quantitative reverse transcriptase PCR (qRT-PCR) can also be used todetermine the expression profiles of marker genes (see, e.g., U.S.Patent Application Publication No. 2005/0048542A1). The first step ingene expression profiling by RT-PCR is the reverse transcription of theRNA template into cDNA, followed by its exponential amplification in aPCR reaction. The two most commonly used reverse transcriptases areavilo myeloblastosis virus reverse transcriptase (AMV-RT) and Moloneymurine leukemia virus reverse transcriptase (MLV-RT). The reversetranscription step is typically primed using specific primers, randomhexamers, or oligo-dT primers, depending on the circumstances and thegoal of expression profiling. For example, extracted RNA can bereverse-transcribed using a GeneAmp RNA PCR kit (Perkin Elmer, Calif.,USA), following the manufacturer's instructions. The derived cDNA canthen be used as a template in the subsequent PCR reaction.

Although the PCR step can use a variety of thermostable DNA-dependentDNA polymerases, it typically employs the Taq DNA polymerase, which hasa 5′-3′ nuclease activity but lacks a 3′-5′ proofreading endonucleaseactivity. Thus, TaqMan® PCR typically utilizes the 5′-nuclease activityof Taq or Tth polymerase to hydrolyze a hybridization probe bound to itstarget amplicon, but any enzyme with equivalent 5′ nuclease activity canbe used. Two oligonucleotide primers are used to generate an amplicontypical of a PCR reaction. A third oligonucleotide, or probe, isdesigned to detect nucleotide sequence located between the two PCRprimers. The probe is non-extendible by Taq DNA polymerase enzyme, andis labeled with a reporter fluorescent dye and a quencher fluorescentdye. Any laser-induced emission from the reporter dye is quenched by thequenching dye when the two dyes are located close together as they areon the probe. During the amplification reaction, the Taq DNA polymeraseenzyme cleaves the probe in a template-dependent manner. The resultantprobe fragments disassociate in solution, and signal from the releasedreporter dye is free from the quenching effect of the secondfluorophore. One molecule of reporter dye is liberated for each newmolecule synthesized, and detection of the unquenched reporter dyeprovides the basis for quantitative interpretation of the data.

TaqMan® RT-PCR can be performed using commercially available equipment,such as, for example, ABI PRISM 7700™. Sequence Detection System™(Perkin-Elmer-Applied Biosystems, Foster City, Calif., USA), orLightcycler (Roche Molecular Biochemicals, Mannheim, Germany). In apreferred embodiment, the 5′ nuclease procedure is run on a real-timequantitative PCR device such as the ABI PRISM 7700™ Sequence DetectionSystem™. The system consists of a thermocycler, laser, charge-coupleddevice (CCD), camera and computer. The system includes software forrunning the instrument and for analyzing the data.

5′-Nuclease assay data are initially expressed as Ct, or the thresholdcycle. Fluorescence values are recorded during every cycle and representthe amount of product amplified to that point in the amplificationreaction. The point when the fluorescent signal is first recorded asstatistically significant is the threshold cycle (Ct).

To minimize errors and the effect of sample-to-sample variation, RT-PCRis usually performed using an internal standard. The ideal internalstandard is expressed at a constant level among different tissues, andis unaffected by the experimental treatment. RNAs most frequently usedto normalize patterns of gene expression are mRNAs for the housekeepinggenes glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) and β-actin.

A more recent variation of the RT-PCR technique is the real timequantitative PCR, which measures PCR product accumulation through adual-labeled fluorogenic probe (i.e., TaqMan® probe). Real time PCR iscompatible both with quantitative competitive PCR, where internalcompetitor for each target sequence is used for normalization, and withquantitative comparative PCR using a normalization gene contained withinthe sample, or a housekeeping gene for RT-PCR. For further details see,e.g. Held et al., Genome Research 6:986-994 (1996).

5.2.5.8. Detection and Quantification of Protein

Measurement of the translational state may be performed according toseveral methods. For example, whole genome monitoring of protein (e.g.,the “proteome,”) can be carried out by constructing a microarray inwhich binding sites comprise immobilized, preferably monoclonal,antibodies specific to a plurality of protein species encoded by thecell genome. Preferably, antibodies are present for a substantialfraction of the encoded proteins, or at least for those proteinsrelevant to the action of a drug of interest. Methods for makingmonoclonal antibodies are well known (see, e.g., Harlow and Lane, 1988,Antibodies: A Laboratory Manual, Cold Spring Harbor, N.Y., which isincorporated in its entirety for all purposes). In one embodiment,monoclonal antibodies are raised against synthetic peptide fragmentsdesigned based on genomic sequence of the cell. With such an antibodyarray, proteins from the cell are contacted to the array and theirbinding is assayed with assays known in the art.

Immunoassays known to one of skill in the art can be used to detect andquantify protein levels. For example, ELISAs can be used to detect andquantify protein levels. ELISAs comprise preparing antigen, coating thewell of a 96 well microtiter plate with the antigen, adding the antibodyof interest conjugated to a detectable compound such as an enzymaticsubstrate (e.g., horseradish peroxidase or alkaline phosphatase) to thewell and incubating for a period of time, and detecting the presence ofthe antigen. In ELISAs the antibody of interest does not have to beconjugated to a detectable compound; instead, a second antibody (whichrecognizes the antibody of interest) conjugated to a detectable compoundmay be added to the well. Further, instead of coating the well with theantigen, the antibody may be coated to the well. In this case, a secondantibody conjugated to a detectable compound may be added following theaddition of the antigen of interest to the coated well. One of skill inthe art would be knowledgeable as to the parameters that can be modifiedto increase the signal detected as well as other variations of ELISAsknown in the art. In a preferred embodiment, an ELISA may be performedby coating a high binding 96-well microtiter plate (Costar) with 2 μg/mlof rhu-IL-9 in PBS overnight. Following three washes with PBS, the plateis incubated with three-fold serial dilutions of Fab at 25° C. for 1hour. Following another three washes of PBS, 1 μg/ml anti-humankappa-alkaline phosphatase-conjugate is added and the plate is incubatedfor 1 hour at 25° C. Following three washes with PBST, the alkalinephosphatase activity is determined in 50 μl/AMP/PPMP substrate. Thereactions are stopped and the absorbance at 560 nm is determined with aVMAX microplate reader. For further discussion regarding ELISAs see,e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology,Vol. 1, John Wiley & Sons, Inc., New York at 11.2.1.

Protein levels may be determined by Western blot analysis. Further,protein levels as well as the phosphorylation of proteins can bedetermined by immunoprecitation followed by Western blot analysisImmunoprecipitation protocols generally comprise lysing a population ofcells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100,1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphateat pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/orprotease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate),adding the antibody of interest to the cell lysate, incubating for aperiod of time (e.g., 1 to 4 hours) at 40° C., adding protein A and/orprotein G sepharose beads to the cell lysate, incubating for about anhour or more at 40° C., washing the beads in lysis buffer andresuspending the beads in SDS/sample buffer. The ability of the antibodyof interest to immunoprecipitate a particular antigen can be assessedby, e.g., western blot analysis. One of skill in the art would beknowledgeable as to the parameters that can be modified to increase thebinding of the antibody to an antigen and decrease the background (e.g.,pre-clearing the cell lysate with sepharose beads). For furtherdiscussion regarding immunoprecipitation protocols see, e.g., Ausubel etal, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, JohnWiley & Sons, Inc., New York at 10.16.1.

Western blot analysis generally comprises preparing protein samples,electrophoresis of the protein samples in a polyacrylamide gel (e.g.,8%-20% SDS-PAGE depending on the molecular weight of the antigen),transferring the protein sample from the polyacrylamide gel to amembrane such as nitrocellulose, PVDF or nylon, incubating the membranein blocking solution (e.g., PBS with 3% BSA or non-fat milk), washingthe membrane in washing buffer (e.g., PBS-Tween 20), incubating themembrane with primary antibody (the antibody of interest) diluted inblocking buffer, washing the membrane in washing buffer, incubating themembrane with a secondary antibody (which recognizes the primaryantibody, e.g., an anti-human antibody) conjugated to an enzymaticsubstrate (e.g., horseradish peroxidase or alkaline phosphatase) orradioactive molecule (e.g., ³²P or ¹²⁵I) diluted in blocking buffer,washing the membrane in wash buffer, and detecting the presence of theantigen. One of skill in the art would be knowledgeable as to theparameters that can be modified to increase the signal detected and toreduce the background noise. For further discussion regarding westernblot protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols inMolecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10.8.1.

Protein expression levels can also be separated by two-dimensional gelelectrophoresis systems. Two-dimensional gel electrophoresis iswell-known in the art and typically involves iso-electric focusing alonga first dimension followed by SDS-PAGE electrophoresis along a seconddimension. See, e.g., Hames et al., 1990, Gel Electrophoresis ofProteins: A Practical Approach, IRL Press, New York; Shevchenko et al.,1996, Proc. Natl. Acad. Sci. USA 93:1440-1445; Sagliocco et al., 1996,Yeast 12:1519-1533; Lander, 1996, Science 274:536-539. The resultingelectropherograms can be analyzed by numerous techniques, including massspectrometric techniques, Western blotting and immunoblot analysis usingpolyclonal and monoclonal antibodies, and internal and N-terminalmicro-sequencing.

5.3. Treating CML by Modulating Expression and/or Activity of CMLProgression Genes and/or their Products

The invention provides methods and compositions for utilizing CML targetgenes listed in Table 3 or 5a or 5b and or imatinib resistance geneslisted in Table 4 in treating CML. The methods and compositions are usedfor treating CML patient exhibiting aberrant regulation of one or moreCML target/progression genes or IM resistance genes by modulating theexpression and/or activity of such genes and/or the encoded proteins.The methods and composition can be used in conjunction with other CMLtreatment, e.g., imatinib mesylate. The compositions (e.g., agents thatmodulate expression and/or activity of the CML target gene or geneproduct) of the invention are preferably purified. In the following, forsimplicity reasons, the methods are often described with reference toCML target gene(s). It will be understood that the methods are equallyapplicable to CML progression genes and IM resistance genes.

In one embodiment, the invention provides methods and compositions fortreating a CML patient exhibiting an aberrant up-regulation of a CMLtarget gene by reducing the expression and/or activity of the gene,and/or its encoded protein by at least 2 fold, 3 fold, 4 fold, 6 fold, 8fold or 9 fold.

In a specific embodiment, the invention provides methods andcompositions for treating a CML patient exhibiting an aberrantup-regulation of a CML target gene as listed in Table 5a or 5b byreducing the expression and/or activity of the gene, and/or its encodedprotein.

In another embodiment, the invention provides methods and compositionsfor treating a CML patient exhibiting an aberrant down-regulation of aCML target gene by enhancing the expression and/or activity of the gene,and/or its encoded protein by at least 2 fold, 3 fold, 4 fold, 6 fold, 8fold or 9 fold.

In a specific embodiment, the invention provides methods andcompositions for treating a CML patient exhibiting an aberrantdown-regulation of a CML target gene as listed in Table 5a or 5b byenhancing the expression and/or activity of the gene, and/or its encodedprotein.

In a specific embodiment, the invention provides a method for treatingCML by administering to a patient (i) an agent that modulates theexpression and/or activity of an imatinib resistance gene and/or theencoded protein, and (ii) a therapeutically sufficient amount ofimatinib mesylate.

In another embodiment, the invention provides methods and compositionsfor treating a CML patient exhibiting aberrant regulation of a pluralityof different CML target gene as listed in Tables 5a and 5b by modulatingthe expression and/or activity of the plurality of genes, and/or itsencoded proteins. In one embodiment, a CML patient exhibiting aberrantup-regulation of a plurality of CML progression gene listed in Tables 5aand 5b, e.g. 2, 3, 4, 5, 10 or more different CML target genes, istreated by administering to the patient one or more agents that reducethe expression and/or activities of these genes, and/or their encodedproteins.

A variety of therapeutic approaches may be used in accordance with theinvention to modulate expression of a CML target gene or imatinibresistance gene and/or its encoded protein in vivo. For example, siRNAmolecules may be engineered and used to silence a CML target gene invivo. Antisense DNA molecules may also be engineered and used to blocktranslation of a CML target mRNA in vivo. Alternatively, ribozymemolecules may be designed to cleave and destroy the mRNAs of a CMLtarget gene in vivo. In another alternative, oligonucleotides designedto hybridize to the 5′ region of the CML target gene (including theregion upstream of the coding sequence) and form triple helix structuresmay be used to block or reduce transcription of the CML target gene. Theexpression and/or activity of a CML target protein can be modulatedusing antibody, peptide or polypeptide molecules, and small organic orinorganic molecules. In the following, for simplicity, methods aredescribed in reference to a CML target gene or protein. These methodsare equally applicable to imatinib resistance genes.

In a preferred embodiment, RNAi is used to knock down the expression ofa CML target gene. In one embodiment, double-stranded RNA molecules of21-23 nucleotides which hybridize to a homologous region of mRNAstranscribed from the CML target gene are used to degrade the mRNAs,thereby “silence” the expression of the CML target gene. The method canbe used to reduce expression levels of aberrantly up-regulated CMLtarget genes. Preferably, the dsRNAs have a hybridizing region, e.g., a19-nucleotide double-stranded region, which is complementary to asequence of the coding sequence of the CML target gene. Any siRNA thattargets an appropriate coding sequence of a CML target gene and exhibita sufficient level of silencing can be used in the invention. Asexemplary embodiments, 21-nucleotide double-stranded siRNAs targetingthe coding regions of a CML target gene are designed according toselection rules known in the art (see, e.g., Elbashir et al., 2002,Methods 26:199-213; International Application No. PCT/US04/35636, filedOct. 27, 2004, each of which is incorporated herein by reference in itsentirety). In a preferred embodiment, the siRNA or siRNAs specificallyinhibit the translation or transcription of a CML target protein withoutsubstantially affecting the translation or transcription of genesencoding other protein kinases in the same kinase family. In a specificembodiment, siRNAs targeting an up-regulated gene listed in Table 4 areused to silence the respective CML target genes.

The invention also provides methods and compositions for treating a CMLpatient exhibiting aberrant up-regulation of a plurality of CML targetgenes as listed in Tables 5a and 5b by reducing the expression and/oractivities of these genes, and/or their encoded proteins. In oneembodiment, a CML patient exhibiting aberrant up-regulation of aplurality of CML target gene listed in Tables 5a and 5b, e.g. 2, 3, 4,5, 10 or more different CML target genes, is treated by administering tothe patient one or more agents that reduce the expression and/oractivities of these genes, and/or their encoded proteins. In a preferredembodiment, an siRNA is used to silence the plurality of different CMLtarget genes. The sequence of the siRNA is chosen such that thetranscript of each of the genes comprises a nucleotide sequence that isidentical to a central contiguous nucleotide sequence of at least 11nucleotides of the sense strand or the antisense strand of the siRNA,and/or comprises a nucleotide sequence that is identical to a contiguousnucleotide sequence of at least 9 nucleotides at the 3′ end of the sensestrand or the antisense strand of the siRNA. Thus, when administrated tothe patient, the siRNA silences all of the plurality of genes in cellsof the patient. In preferred embodiments, the central contiguousnucleotide sequence of the siRNA that is identical to one or more CMLtarget genes is 11-15, 14-15, 11, 12, or 13 nucleotides in length. Inother preferred embodiments, the 3′ contiguous nucleotide sequence ofthe siRNA that is identical to one or more CML target genes is 9-15,9-12, 11, 10, or 9 nucleotides in length. The length and nucleotide basesequence of the target sequence of each different target gene, i.e., thesequence of the gene that is identical to an appropriate sense orantisense sequence of the siRNA, can be different from gene to gene. Forexample, gene A may have a sequence of 11 nucleotides identical to thenucleotide sequence 3-13 of the sense strand of the siRNA, while gene Bmay have a sequence of 12 nucleotides identical to the nucleotidesequence 4-15 of the sense strand of the siRNA. Thus, a single siRNA maybe designed to silence a large number of CML target genes in cells.

RNAi can be carried out using any standard method for introducingnucleic acids into cells. In one embodiment, gene silencing is inducedby presenting the cell with one or more siRNAs targeting the CML targetgene (see, e.g., Elbashir et al., 2001, Nature 411, 494-498; Elbashir etal., 2001, Genes Dev. 15, 188-200, all of which are incorporated byreference herein in their entirety). The siRNAs can be chemicallysynthesized, or derived from cleavage of double-stranded RNA byrecombinant Dicer. Another method to introduce a double stranded DNA(dsRNA) for silencing of the CML target gene is shRNA, for short hairpinRNA (see, e.g., Paddison et al., 2002, Genes Dev. 16, 948-958;Brummelkamp et al., 2002, Science 296, 550-553; Sui, G. et al. 2002,Proc. Natl. Acad. Sci. USA 99, 5515-5520, all of which are incorporatedby reference herein in their entirety). In this method, a siRNAtargeting a CML target gene is expressed from a plasmid (or virus) as aninverted repeat with an intervening loop sequence to form a hairpinstructure. The resulting RNA transcript containing the hairpin issubsequently processed by Dicer to produce siRNAs for silencing.Plasmid- or virus-based shRNAs can be expressed stably in cells,allowing long-term gene silencing in cells both in vitro and in vivo(see, McCaffrey et al. 2002, Nature 418, 38-39; Xia et al., 2002, Nat.Biotech. 20, 1006-1010; Lewis et al., 2002, Nat. Genetics 32, 107-108;Rubinson et al., 2003, Nat. Genetics 33, 401-406; Tiscornia et al.,2003, Proc. Natl. Acad. Sci. USA 100, 1844-1848, all of which areincorporated by reference herein in their entirety). Such plasmid- orvirus-based shRNAs can be delivered using a gene therapy approach.SiRNAs targeting the CML target gene can also be delivered to an organor tissue in a mammal, such a human, in vivo (see, e.g., Song et al.2003, Nat. Medicine 9, 347-351; Sorensen et al., 2003, J. Mol. Biol.327, 761-766; Lewis et al., 2002, Nat. Genetics 32, 107-108, all ofwhich are incorporated by reference herein in their entirety). In thismethod, a solution of siRNA is injected intravenously into the mammalThe siRNA can then reach an organ or tissue of interest and effectivelyreduce the expression of the target gene in the organ or tissue of themammal

In preferred embodiments, an siRNA pool (mixture) containing at least k(k=2, 3, 4, 5, 6 or 10) different siRNAs targeting a CML target gene atdifferent sequence regions is used to silence the gene. In a preferredembodiment, the total siRNA concentration of the pool is about the sameas the concentration of a single siRNA when used individually. As usedherein, the word “about” with reference to concentration means within20%. Preferably, the total concentration of the pool of siRNAs is anoptimal concentration for silencing the intended target gene. An optimalconcentration is a concentration further increase of which does notincrease the level of silencing substantially. In one embodiment, theoptimal concentration is a concentration further increase of which doesnot increase the level of silencing by more than 5%, 10% or 20%. In apreferred embodiment, the composition of the pool, including the numberof different siRNAs in the pool and the concentration of each differentsiRNA, is chosen such that the pool of siRNAs causes less than 30%, 20%,10% or 5%, 1%, 0.1% or 0.01% of silencing of any off-target genes (e.g.,as determined by standard nucleic acid assay, e.g., PCR). In anotherpreferred embodiment, the concentration of each different siRNA in thepool of different siRNAs is about the same. In still another preferredembodiment, the respective concentrations of different siRNAs in thepool are different from each other by less than 5%, 10%, 20% or 50% ofthe concentration of any one siRNA or said total siRNA concentration ofsaid different siRNAs. In still another preferred embodiment, at leastone siRNA in the pool of different siRNAs constitutes more than 90%,80%, 70%, 50%, or 20% of the total siRNA concentration in the pool. Instill another preferred embodiment, none of the siRNAs in the pool ofdifferent siRNAs constitutes more than 90%, 80%, 70%, 50%, or 20% of thetotal siRNA concentration in the pool. In other embodiments, each siRNAin the pool has a concentration that is lower than the optimalconcentration when used individually. In a preferred embodiment, eachdifferent siRNA in the pool has an concentration that is lower than theconcentration of the siRNA that is effective to achieve at least 30%,50%, 75%, 80%, 85%, 90% or 95% silencing when used in the absence ofother siRNAs or in the absence of other siRNAs designed to silence thegene. In another preferred embodiment, each different siRNA in the poolhas a concentration that causes less than 30%, 20%, 10% or 5% ofsilencing of the gene when used in the absence of other siRNAs or in theabsence of other siRNAs designed to silence the gene. In a preferredembodiment, each siRNA has a concentration that causes less than 30%,20%, 10% or 5% of silencing of the target gene when used alone, whilethe plurality of siRNAs causes at least 80% or 90% of silencing of thetarget gene. In specific embodiments, a pool containing the 3 differentis used for targeting a CML target gene. More detailed descriptions oftechniques for carrying out RNAi are also presented in Section 5.6.

In other embodiments, antisense, ribozyme, and triple helix formingnucleic acid are designed to inhibit the translation or transcription ofa CML target protein or gene with minimal effects on the expression ofother genes that may share one or more sequence motif with the CMLtarget gene. To accomplish this, the oligonucleotides used should bedesigned on the basis of relevant sequences unique to a CML target gene.In one embodiment, the oligonucleotide used specifically inhibits thetranslation or transcription of a CML target protein or gene withoutsubstantially affecting the translation or transcription of otherproteins in the same protein family.

For example, and not by way of limitation, the oligonucleotides shouldnot fall within those regions where the nucleotide sequence of a CMLtarget gene is most homologous to that of other genes. In the case ofantisense molecules, it is preferred that the sequence be at least 18nucleotides in length in order to achieve sufficiently strong annealingto the target mRNA sequence to prevent translation of the sequence.Izant et al., 1984, Cell, 36:1007-1015; Rosenberg et al., 1985, Nature,313:703-706.

Ribozymes are RNA molecules which possess highly specificendoribonuclease activity. Hammerhead ribozymes comprise a hybridizingregion which is complementary in nucleotide sequence to at least part ofthe target RNA, and a catalytic region which is adapted to cleave thetarget RNA. The hybridizing region contains nine (9) or morenucleotides. Therefore, the hammerhead ribozymes useful for targeting aCML target gene having a hybridizing region which is complementary tothe sequences of the target gene and is at least nine nucleotides inlength. The construction and production of such ribozymes is well knownin the art and is described more fully in Haseloff et al., 1988, Nature,334:585-591.

The ribozymes of the present invention also include RNAendoribonucleases (hereinafter “Cech-type ribozymes”) such as the onewhich occurs naturally in Tetrahymena Thermophila (known as the IVS, orL-19 IVS RNA) and which has been extensively described by Thomas Cechand collaborators (Zaug, et al., 1984, Science, 224:574-578; Zaug andCech, 1986, Science, 231:470-475; Zaug, et al., 1986, Nature,324:429-433; published International patent application No. WO 88/04300by University Patents Inc.; Been et al., 1986, Cell, 47:207-216). TheCech endoribonucleases have an eight base pair active site whichhybridizes to a target RNA sequence whereafter cleavage of the targetRNA takes place.

In the case of oligonucleotides that hybridize to and form triple helixstructures at the 5′ terminus of a CML target gene and can be used toblock transcription, it is preferred that they be complementary to thosesequences in the 5′ terminus of a CML target gene which are not presentin other related genes. It is also preferred that the sequences notinclude those regions of the promoter of a CML target gene which areeven slightly homologous to that of other related genes.

The foregoing compounds can be administered by a variety of methodswhich are known in the art including, but not limited to the use ofliposomes as a delivery vehicle. Naked DNA or RNA molecules may also beused where they are in a form which is resistant to degradation such asby modification of the ends, by the formation of circular molecules, orby the use of alternate bonds including phosphothionate andthiophosphoryl modified bonds. In addition, the delivery of nucleic acidmay be by facilitated transport where the nucleic acid molecules areconjugated to poly-lysine or transferrin. Nucleic acid may also betransported into cells by any of the various viral carriers, includingbut not limited to, retrovirus, vaccinia, AAV, and adenovirus.

Alternatively, a recombinant nucleic acid molecule which encodes, or is,such antisense nucleic acid, ribozyme, triple helix forming nucleicacid, or nucleic acid molecule of a CML target gene can be constructed.This nucleic acid molecule may be either RNA or DNA. If the nucleic acidencodes an RNA, it is preferred that the sequence be operativelyattached to a regulatory element so that sufficient copies of thedesired RNA product are produced. The regulatory element may permiteither constitutive or regulated transcription of the sequence. In vivo,that is, within the cells or cells of an organism, a transfer vectorsuch as a bacterial plasmid or viral RNA or DNA, encoding one or more ofthe RNAs, may be transfected into cells e.g. (Llewellyn et al., 1987, J.Mol. Biol., 195:115-123; Hanahan et al. 1983, J. Mol. Biol.,166:557-580). Once inside the cell, the transfer vector may replicate,and be transcribed by cellular polymerases to produce the RNA or it maybe integrated into the genome of the host cell. Alternatively, atransfer vector containing sequences encoding one or more of the RNAsmay be transfected into cells or introduced into cells by way ofmicromanipulation techniques such as microinjection, such that thetransfer vector or a part thereof becomes integrated into the genome ofthe host cell.

The activity of a CML target protein can be modulated by modulating theinteraction of a CML target protein with its binding partners. In oneembodiment, agents, e.g., antibodies, peptides, aptamers, small organicor inorganic molecules, can be used to inhibit binding of a CML targetprotein binding partner to treat CML. In another embodiment, agents,e.g., antibodies, aptamers, small organic or inorganic molecules, can beused to inhibit the activity of a CML target protein to treat CML.

In other embodiments, when the CML target protein is a kinase, theinvention provides small molecule inhibitors of the CML target protein.A small molecule inhibitor is a low molecular weight phosphorylationinhibitor. As used herein, a small molecule refers to an organic orinorganic molecule having a molecular weight is under 1000 Daltons,preferably in the range between 300 to 700 Daltons, which is not anucleic acid molecule or a peptide molecule. The small molecule can benaturally occurring, e.g., extracted from plant or microorganisms, ornon-naturally occurring, e.g., generated de novo by synthesis. A smallmolecule that is an inhibitor can be used to block a cellular processthat dependent on a CML target protein. In one embodiment, theinhibitors are substrate mimics. In a preferred embodiment, theinhibitor of the CML target proteins is an ATP mimic. In one embodiment,such ATP mimics possess at least two aromatic rings. In a preferredembodiment, the ATP mimic comprises a moiety that forms extensivecontacts with residues lining the ATP binding cleft of the CML targetprotein and/or peptide segments just outside the cleft, therebyselectively blocking the ATP binding site of the CML target protein.Minor structural differences from ATP can be introduced into the ATPmimic based on the peptide segments just outside the cleft. Suchdifferences can lead to specific hydrogen bonding and hydrophobicinteractions with the peptide segments just outside the cleft.

In still other embodiments, antibodies that specifically bind the CMLtarget protein are used. In a preferred embodiment, the inventionprovides antibodies that specifically bind the extracellular domain of aCML target protein that is a receptor. Antibodies that specifically binda target can be obtained using standard method known in the art, e.g., amethod described in Section 5.8.

In one embodiment, an antibody-drug conjugate comprising an antibodythat specifically binds a CML target protein is used. The efficacy ofthe antibodies that targets specific molecules expressed by advancedphase immature myeloid cells can be increased by attaching toxins tothem. Existing immunotoxins are based on bacterial toxins likepseudomonas exotoxin, plant exotoxin like ricin or radio-nucleotides.The toxins are chemically conjugated to a specific ligand such as thevariable domain of the heavy or light chain of the monoclonal antibody.Normal cells lacking the cancer specific antigens are not targeted bythe targeted antibody. In a preferred embodiment, the CML target proteintarget is PRAME.

In other embodiments, a peptide and peptidomimetic that interferes withthe interaction of a CML target protein with its interaction partner isused. A peptide preferably has a size of at least 5, 10, 15, 20 or 30amino acids. Such a peptide or peptidomimetic can be designed by aperson skilled in the art based on the sequence and structure of a CMLtarget protein. In one embodiment, a peptide or peptidomimetic thatinterferes with substrate binding of a CML target protein is used. Inanother embodiment, peptide or peptidomimetic that interferes with thebinding of a signal molecule to a CML target protein is used. In someembodiments of the invention, a fragment or polypeptide of at least 5,10, 20, 50, 100 amino acids in length of a CML target protein are used.In a specific embodiment, a peptide or peptidomimetic that interfereswith the interaction with PRAME is used. The peptide can be prepared bystandard method known in the art.

In another embodiment, a dominant negative mutant of a CML targetprotein is used to reduce activity of a CML target protein. Such adominant negative mutant can be designed by a person skilled in the artbased on the sequence and structure of a CML target protein. In oneembodiment, a dominant negative mutant that interferes with substratebinding of a CML target protein is used. In another embodiment, adominant negative mutant that interferes with the binding of a signalmolecule to a CML target protein is used. In a preferred embodiment, theinvention provides a dominant negative mutant that comprises theC-terminal region of a CML target protein. In another embodiment, theinvention provides a dominant negative mutant that comprises theN-terminal region of the CML target protein.

Gene therapy can be used for delivering any of the above describednucleic acid and protein/peptide therapeutics into target cells. Genetherapy is particularly useful for enhancing aberrantly down-regulatedgenes. Exemplary methods for carrying out gene therapy are describedbelow. For general reviews of the methods of gene therapy, see Goldspielet al., 1993, Clinical Pharmacy 12:488-505; Wu and Wu, 1991, Biotherapy3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol. 32:573-596;Mulligan, 1993, Science 260:926-932; and Morgan and Anderson, 1993, Ann.Rev. Biochem. 62:191-217; May, 1993, TIBTECH 11(5):155-215). Methodscommonly known in the art of recombinant DNA technology which can beused are described in Ausubel et al. (eds.), 1993, Current Protocols inMolecular Biology, John Wiley & Sons, New York; and Kriegler, 1990, GeneTransfer and Expression, A Laboratory Manual, Stockton Press, New York.

In a preferred embodiment, the therapeutic comprises a nucleic acid thatis part of an expression vector that expresses a the therapeutic nucleicacid or peptide/polypeptide in a suitable host. In particular, such anucleic acid has a promoter operably linked to the coding region, saidpromoter being inducible or constitutive, and, optionally,tissue-specific. In another particular embodiment, a nucleic acidmolecule is used in which the coding sequences and any other desiredsequences are flanked by regions that promote homologous recombinationat a desired site in the genome, thus providing for intrachromosomalexpression of the CML target nucleic acid (see e.g., Koller andSmithies, 1989, Proc. Natl. Acad. Sci. U.S.A. 86:8932-8935; Zijlstra etal., 1989, Nature 342:435-438).

Delivery of the nucleic acid into a patient may be either direct, inwhich case the patient is directly exposed to the nucleic acid ornucleic acid-carrying vector, or indirect, in which case, cells arefirst transformed with the nucleic acid in vitro, then transplanted intothe patient. These two approaches are known, respectively, as in vivo orex vivo gene therapy.

In a specific embodiment, the nucleic acid is directly administered invivo, where it is expressed to produce the encoded product. This can beaccomplished by any of numerous methods known in the art, e.g., byconstructing it as part of an appropriate nucleic acid expression vectorand administering it so that it becomes intracellular, e.g., byinfection using a defective or attenuated retroviral or other viralvector (see U.S. Pat. No. 4,980,286), or by direct injection of nakedDNA, or by use of microparticle bombardment (e.g., a gene gun;Biolistic, Dupont), or coating with lipids or cell-surface receptors ortransfecting agents, encapsulation in liposomes, microparticles, ormicrocapsules, or by administering it in linkage to a peptide which isknown to enter the nucleus, by administering it in linkage to a ligandsubject to receptor-mediated endocytosis (see e.g., Wu and Wu, 1987, J.Biol. Chem. 262:4429-4432) (which can be used to target cell typesspecifically expressing the receptors), etc. In another embodiment, anucleic acid-ligand complex can be formed in which the ligand comprisesa fusogenic viral peptide to disrupt endosomes, allowing the nucleicacid to avoid lysosomal degradation. In yet another embodiment, thenucleic acid can be targeted in vivo for cell specific uptake andexpression, by targeting a specific receptor (see, e.g., PCTPublications WO 92/06180 dated Apr. 16, 1992 (Wu et al.); WO 92/22635dated Dec. 23, 1992 (Wilson et al.); WO92/20316 dated Nov. 26, 1992(Findeis et al.); WO93/14188 dated Jul. 22, 1993 (Clarke et al.), WO93/20221 dated Oct. 14, 1993 (Young)). Alternatively, the nucleic acidcan be introduced intracellularly and incorporated within host cell DNAfor expression, by homologous recombination (Koller and Smithies, 1989,Proc. Natl. Acad. Sci. U.S.A. 86:8932-8935; Zijlstra et al., 1989,Nature 342:435-438).

In a specific embodiment, a viral vector that contains the nucleic acidof a CML target gene is used. For example, a retroviral vector can beused (see Miller et al., 1993, Meth. Enzymol. 217:581-599). Theseretroviral vectors have been modified to delete retroviral sequencesthat are not necessary for packaging of the viral genome and integrationinto host cell DNA. The CML target nucleic acid to be used in genetherapy is cloned into the vector, which facilitates delivery of thegene into a patient. More detail about retroviral vectors can be foundin Boesen et al., 1994, Biotherapy 6:291-302, which describes the use ofa retroviral vector to deliver the mdr1 gene to hematopoietic stem cellsin order to make the stem cells more resistant to chemotherapy. Otherreferences illustrating the use of retroviral vectors in gene therapyare: Clowes et al., 1994, J. Clin. Invest. 93:644-651; Kiem et al.,1994, Blood 83:1467-1473; Salmons and Gunzberg, 1993, Human Gene Therapy4:129-141; and Grossman and Wilson, 1993, Curr. Opin. Genet. and Devel.3:110-114.

Adenoviruses are other viral vectors that can be used in gene therapy.Adenoviruses are especially attractive vehicles for delivering genes torespiratory epithelia. Adenoviruses naturally infect respiratoryepithelia where they cause a mild disease. Other targets foradenovirus-based delivery systems are liver, the central nervous system,endothelial cells, and muscle. Adenoviruses have the advantage of beingcapable of infecting non-dividing cells. Kozarsky and Wilson (1993,Current Opinion in Genetics and Development 3:499-503) present a reviewof adenovirus-based gene therapy. Bout et al. (1994, Human Gene Therapy5:3-10) demonstrated the use of adenovirus vectors to transfer genes tothe respiratory epithelia of rhesus monkeys. Other instances of the useof adenoviruses in gene therapy can be found in Rosenfeld et al., 1991,Science 252:431-434; Rosenfeld et al., 1992, Cell 68:143-155; andMastrangeli et al., 1993, J. Clin. Invest. 91:225-234.

Adeno-associated virus (AAV) has also been proposed for use in genetherapy (Walsh et al., 1993, Proc. Soc. Exp. Biol. Med. 204:289-300).

Another approach to gene therapy involves transferring a gene to cellsin tissue culture by such methods as electroporation, lipofection,calcium phosphate mediated transfection, or viral infection. Usually,the method of transfer includes the transfer of a selectable marker tothe cells. The cells are then placed under selection to isolate thosecells that have taken up and are expressing the transferred gene. Thosecells are then delivered to a patient.

In this embodiment, the nucleic acid is introduced into a cell prior toadministration in vivo of the resulting recombinant cell. Suchintroduction can be carried out by any method known in the art,including but not limited to transfection, electroporation,microinjection, infection with a viral or bacteriophage vectorcontaining the nucleic acid sequences, cell fusion, chromosome-mediatedgene transfer, microcell-mediated gene transfer, spheroplast fusion,etc. Numerous techniques are known in the art for the introduction offoreign genes into cells (see e.g., Loeffler and Behr, 1993, Meth.Enzymol. 217:599-618; Cohen et al., 1993, Meth. Enzymol. 217:618-644;Cline, 1985, Pharmac. Ther. 29:69-92) and may be used in accordance withthe present invention, provided that the necessary developmental andphysiological functions of the recipient cells are not disrupted. Thetechnique should provide for the stable transfer of the nucleic acid tothe cell, so that the nucleic acid is expressible by the cell andpreferably heritable and expressible by its cell progeny.

The resulting recombinant cells can be delivered to a patient by variousmethods known in the art. In a preferred embodiment, epithelial cellsare injected, e.g., subcutaneously. In another embodiment, recombinantskin cells may be applied as a skin graft onto the patient. Recombinantblood cells (e.g., hematopoietic stem or progenitor cells) arepreferably administered intravenously. The amount of cells envisionedfor use depends on the desired effect, patient state, etc., and can bedetermined by one skilled person in the art.

Cells into which a nucleic acid can be introduced for purposes of genetherapy encompass any desired, available cell type, and include but arenot limited to epithelial cells, endothelial cells, keratinocytes,fibroblasts, muscle cells, hepatocytes; blood cells such as Tlymphocytes, B lymphocytes, monocytes, macrophages, neutrophils,eosinophils, megakaryocytes, granulocytes; various stem or progenitorcells, in particular hematopoietic stem or progenitor cells, e.g., asobtained from bone marrow, umbilical cord blood, peripheral blood, fetalliver, etc.

In a preferred embodiment, the cell used for gene therapy is autologousto the patient.

In an embodiment in which recombinant cells are used in gene therapy, anucleic acid is introduced into the cells such that it is expressible bythe cells or their progeny, and the recombinant cells are thenadministered in vivo for therapeutic effect. In a specific embodiment,stem or progenitor cells are used. Such stem cells can be hematopoieticstem cells (HSC).

Any technique which provides for the isolation, propagation, andmaintenance in vitro of HSC can be used in this embodiment of theinvention. Techniques by which this may be accomplished include (a) theisolation and establishment of HSC cultures from bone marrow cellsisolated from the future host, or a donor, or (b) the use of previouslyestablished long-term HSC cultures, which may be allogeneic orxenogeneic. Non-autologous HSC are used preferably in conjunction with amethod of suppressing transplantation immune reactions of the futurehost/patient. In a particular embodiment of the present invention, humanbone marrow cells can be obtained from the posterior iliac crest byneedle aspiration (see e.g., Kodo et al., 1984, J. Clin. Invest.73:1377-1384). The HSCs can be made highly enriched or in substantiallypure form. This enrichment can be accomplished before, during, or afterlong-term culturing, and can be done by any techniques known in the art.Long-term cultures of bone marrow cells can be established andmaintained by using, for example, modified Dexter cell culturetechniques (Dexter et al., 1977, J. Cell Physiol. 91:335) orWitlock-Witte culture techniques (Witlock and Witte, 1982, Proc. Natl.Acad. Sci. U.S.A. 79:3608-3612).

In a specific embodiment, the nucleic acid to be introduced for purposesof gene therapy comprises an inducible promoter operably linked to thecoding region, such that expression of the nucleic acid is controllableby controlling the presence or absence of the appropriate inducer oftranscription.

The methods and/or compositions described above for modulating theexpression and/or activity of a CML target gene or CML target proteinmay be used to treat patients in conjunction with a chemotherapeuticagent, e.g., Gleevec™

The effects or benefits of administration of the compositions of theinvention alone or in conjunction with a chemotherapeutic agent can beevaluated by any methods known in the art, e.g., by methods that arebased on measuring the survival rate, side effects, dosage requirementof the chemotherapeutic agent, or any combinations thereof. If theadministration of the compositions of the invention achieves any one ormore benefits in a patient, such as increasing the survival rate,decreasing side effects, lowing the dosage requirement for thechemotherapeutic agent, the compositions of the invention are said tohave augmented a chemotherapy, and the method is said to have efficacy.

5.4. Diagnosis and Treatment of CML by Targeting Cell Surface ExpressedPRAME

The present invention provides methods and compositions for diagnosisand treatment of CML by targeting PRAME (GenBank® accession no.NM_(—)006115) on cell surfaces of advanced phase hematopoetic stem cellsand immature myeloid cells. PRAME is known to be expressed in testis andto expressed at a low level in endometrium, adrenals and ovaries, and isnot expressed in other normal tissues. The inventors have found thatPRAME is significantly overexpressed in advanced phase CML cells ascompared to chronic phase CML cells. Thus, methods and compositions thattarget PRAME can be used for detecting advanced phase CML cells and fortreating CML by selectively targeting advanced phase CML cells.

5.4.1. Methods of Detecting Advanced Phase CML

Antibodies or labeled antibodies directed against a PRAME(Preferentially Expressed Antigen of Melanoma) can be used forevaluating CML progression, e.g., by detecting the presence of PRAMEprotein on cell surface of hematopoetic stem cells and immature myeloidcells. Such diagnostic/prognostic methods are particularly useful fordetecting CML progression in unsorted samples.

The tissue or cell type to be analyzed may include those which are knownto relate to CML, e.g., bone marrow or peripheral blood. The proteinisolation methods employed herein may, for example, be such as thosedescribed in Harlow and Lane (Harlow, E. and Lane, D., 1988,“Antibodies: A Laboratory Manual”, Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y.), which is incorporated herein by reference inits entirety. The isolated cells can be derived from cell culture orfrom a patient. The analysis of cells taken from culture may be anecessary step in the assessment of cells to be used as part of acell-based gene therapy technique or, alternatively, to test the effectof compounds for CML treatment.

In one embodiment, the invention provides a method for diagnosingwhether a patient has advanced phase chronic myeloid leukemia (CML),comprising (a) contacting a cell sample from said patient with anantibody conjugate, said antibody conjugate comprising an antibody thatbinds a PRAME protein conjugated with a label; and (b) detecting saidlabel in said sample, wherein detection of said label above apredetermined threshold indicating said patient has advanced phase CML.Detection of the labeled antibody can be performed using a methoddescribed in Section 5.2.5, supra.

5.4.2. Methods of Treating CML by Targeting PRAME

The invention provides methods and compositions for treating CML bytargeting PRAME expressed on the cell surface.

In one embodiment, the present invention provides methods of usinganti-PRAME antibodies for treatment of a CML patient. In the methods ofthe invention, one or more anti-PRAME antibodies are administered to thepatient. The anti-PRAME antibodies bind to PRAME on the surface ofadvanced phase CML hematopoetic stem cells and/or immature myeloidcells. The binding of anti-PRAME antibodies to PRAME blocks the functionmediated by PRAME, thereby preventing the proliferation of advancedphase hematopoetic stem cells.

In another embodiment, the present invention provides a method fortreatment of CML using an anti-PRAME antibody that belongs to an isotypethat is capable of mediating lysis of cells to which the anti-PRAMEantibody is bound. In a preferred embodiment, the anti-PRAME antibodybelongs to an isotype that binds a growth factor receptor and activatesserum complement and/or mediates antibody dependent cellularcytotoxicity (ADCC) by activating effector cells, e.g., macrophages. Inanother preferred embodiment, the isotype is IgG1, IgG2a, IgG3 or IgM.

In still another embodiment, the anti-PRAME antibodies are used inconjunction with one or more other chemotherapeutic drugs. In suchcombined therapies, the anti-PRAME antibodies can be administered in amanner such as described in Section 5.10.5.

The dosage of the anti-PRAME antibodies can be determined by routineexperiments that are familiar to one skilled in the art. The effects orbenefits of administration of the anti-PRAME antibodies can be evaluatedby any method known in the art.

In another embodiment, an antibody-drug conjugate comprising an antibodythat specifically binds PRAME and a chemotherapeutic drug is used toselectively deliver the chemotherapeutic drug to advanced phase CMLhematopoetic stem cells and/or immature myeloid cells. Chemotherapeuticdrugs normally spread throughout the body, reaching not only theintended target but also healthy cells/organs such as the intestines andhealthy bone marrow, where they kill off normal dividing cells. A drugconjugated to PRAME should be able to selectively target the advancephase CML hematopoetic stem cells and/or immature myeloid cells, thusincreasing the sensitivity and specificity of the drug. For example, ananti-PRAME antibody may be conjugated to a therapeutic moiety such as acytotoxin, e.g., a cytostatic or cytocidal agent, or a radioactive metalion (see, e.g., Section 5.8). Any suitable antibody-drug conjugate,e.g., those described in Section 5.8.3 can be used. Normal hematopoeticstem cells and/or myeloid cells lack PRAME and are not targeted by theantibody.

In still another embodiment, a peptide or a peptidomimetic thatinterferes with the interaction of PRAME with its interaction partner isused. A peptide preferably has a size of at least 5, 10, 15, 20 or 30amino acids. Such a peptide or peptidomimetic can be designed by aperson skilled in the art based on the sequence and structure of PRAME.In some embodiments of the invention, a PRAME fragment of at least 5,10, 20, 50, 100 amino acids in length is used. In a specific embodiment,a peptide or peptidomimetic that interferes with the interaction withPRAME is used. The peptide can be prepared by a standard method known inthe art (see, e.g., Section 5.8.4).

The invention also provides methods for treating CML using fragments ofa PRAME protein as vaccines to elicit an immunotherapeutic response in apatient, e.g., an antibody response and/or a cell mediated immuneresponse. Antibody responses involve the production of antibodies, whichare proteins called immunoglobulins. The antibodies circulate in thebloodstream and permeate the other body fluids, where they bindspecifically to the foreign antigen that elicited them. Binding byantibody inactivates advanced phase CML hematopoetic stem cells and/orimmature myeloid cells by blocking their functions facilitated by PRAME.Antibody binding also marks advanced phase CML hematopoetic stem cellsand/or immature myeloid cells, either by making it easier for aphagocytic cell to ingest them or by activating a system of bloodproteins, collectively called complement, which kills the marked targetcells.

Cell-mediated immune responses to PRAME involve the production ofspecialized cells that react with PRAME antigen on the surface ofadvanced phase CML cells. T lymphocytes, which develop in the thymus,are responsible for cell-mediated immunity. The majority of Tlymphocytes, called helper T cells and suppressor T cells, play aregulatory role in immunity, acting either to enhance or suppress theresponses of other white blood cells. Other T lymphocytes, calledcytotoxic T cells (CTLs), kill virus-infected cells, parasites, andcancer cells. The surface of T cells contains transmembrane proteinscalled T cell receptors that recognize the PRAME antigen on the surfaceof PRAME presenting advanced phase CML cells. T cell receptors areantibody-like proteins. The antigen must be presented to the T cell by aparticular membrane protein, one encoded by a complex of genes calledthe major histocompatibility complex (MHC). Histocompatibility moleculesare expressed on the cells of all higher vertebrates. There are twoprincipal classes of MHC molecules, class I MHC and class II MHC.Cytotoxic T lymphocytes (CTLs) recognize foreign antigens in associationwith class I MHC glycoproteins on the surface of an antigen-presentingcell, whereas helper T cells recognize foreign antigens in associationwith class II MHC glycoproteins on the surface of an antigen-presentingcell. A cytotoxic T lymphocyte will kill an antigen-presenting cell whenit recognizes antigen bound to class I MHC molecules on the surface ofthe antigen-presenting cell. In one embodiment, a PRAME vaccine is usedto elicit production of CTLs.

The PRAME protein fragment or polypeptide can be prepared by a standardmethod known in the art. In a specific embodiment, the fragment is ahuman PRAME protein fragment, or its murine homolog. In anotherembodiment, the vaccine comprises a peptide sequence that is at least30%, 50%, 70%, 90%, or 95% homologous (e.g., over an equal size) to suchfragments of a PRAME protein, e.g., as determined by a BLAST algorithm.In some embodiments, the PRAME protein fragments or polypeptides are atleast 5, 10, 20, 50, 100 amino acids in length.

A peptide or polypeptide which is functionally equivalent to any PRAMEfragment described above can also be used. Such an equivalent PRAMEfragment may contain deletions, additions or substitutions of amino acidresidues within the amino acid sequence encoded by the PRAME genesequence but which result in a silent change, thus producing afunctionally equivalent PRAME protein fragment. Amino acid substitutionsmay be made on the basis of similarity in polarity, charge, solubility,hydrophobicity, hydrophilicity, and/or the amphipathic nature of theresidues involved. Conservative substitutions may be made from amongamino acids of the same polarity. For example, nonpolar (hydrophobic)amino acids include alanine, leucine, isoleucine, valine, proline,phenylalanine, tryptophan, and methionine; polar neutral amino acidsinclude glycine, serine, threonine, cysteine, tyrosine, asparagine, andglutamine; positively charged (basic) amino acids include arginine,lysine, and histidine; and negatively charged (acidic) amino acidsinclude aspartic acid and glutamic acid. “Functionally equivalent”, asutilized herein, refers to a protein fragment capable of exhibiting asubstantially similar in vivo activity as the endogenous PRAME proteinfragment.

The PRAME peptide fragments may be produced by recombinant DNAtechnology using techniques well known in the art (see, e.g., Section5.8.4).

The PRAME peptide can be used in combination with a suitable carrierand/or adjuvant, such as Freund's complete or incomplete adjuvant, or asimilar immunostimulatory agent. An oil/surfactant based adjuvantcomprising one or more surfactants combined with one or morenon-metabolizable mineral oil or metabolizable oil, such as theIncomplete Seppic Adjuvant (Seppic, Paris, France), may be used. AnIncomplete Seppic Adjuvant has a comparable effect as IncompleteFreund's Adjuvant for antibody production, but induces a lowerinflammatory response.

A fragment of a PRAME gene can also be used as a DNA or RNA vaccine. Ina specific embodiment, the fragment of a PRAME gene is a fragment of ahuman PRAME gene, or its murine homolog. The invention also provides anysequence that is at least 30%, 50%_(,) 70%_(,) 90%, or 95% homologous(e.g., over an equal size) to such fragments of a PRAME gene. In someembodiments of the invention, the fragment of a PRAME gene is at least20, 25, 40, 60, 80, 100, 500, 1000 bases in length. Such sequences maybe useful for production of PRAME peptides.

In another embodiment, the present invention provides a naked DNA or RNAvaccine comprising a fragment of a PRAME gene, and uses thereof. ThePRAME DNA fragment can be administered as a vaccine to elicit anti-PRAMEantibodies. The DNA can be converted to RNA for example by subcloningthe DNA into a transcriptional vector, such as pGEM family of plasmidvectors, or under control of a transcriptional promoter of a virus suchas vaccinia, and the RNA used as a naked RNA vaccine. The naked DNA orRNA vaccine can be injected alone, or combined with one or more DNA orRNA vaccines directed to PRAME.

The naked DNA or RNA vaccine of the present invention can beadministered for example intramuscularly, or alternatively, can be usedin nose drops. The DNA or RNA fragment or a portion thereof can beinjected as naked DNA or RNA, as DNA or RNA encapsulated in liposomes,as DNA or RNA entrapped in proteoliposomes containing viral envelopereceptor proteins (Nicolau, C. et al. Proc. Natl. Acad. Sci. U.S.A.1983, 80, 1068; Kanoda, Y., et al. Science 1989, 243, 375; Mannino, R.J. et al. Biotechniques 1988, 6, 682). Alternatively, the DNA can beinjected along with a carrier. A carrier can be a protein or such as acytokine, for example interleukin 2, or a polylysine-glycoproteincarrier (Wu, G. Y. and Wu, C. H. J. Biol. Chem. 1988, 263, 14621), or anonreplicating vector, for example expression vectors containing eitherthe Rous sarcoma virus or cytomegalovirus promoters. Such carrierproteins and vectors and methods for using same are known to a person inthe art (See for example, Acsadi, G. et al. Nature 1991, 352, 815-818).In addition, the DNA or RNA could be coated onto tiny gold beads and thebeads introduced into the skin with, for example, a gene gun (Cohen, J.Science 1993, 259, 1691-1692; Ulmer, J. B. et al. Science 1993, 259,1745-1749).

5.4.3. Depletion of Advanced Phase CML Hematopoetic Stem Cells and/orImmature Myeloid Cells In Vitro

The invention provides methods of depleting advanced phase CMLhematopoetic stem cells and/or immature myeloid cells from bone marrowor blood in vitro (or ex vivo). In particular, the invention providesfor methods of depleting advanced phase CML hematopoetic stem cellsand/or immature myeloid cells by killing them or by separating them frombone marrow or blood. In one embodiment, anti-PRAME antibodies arecombined, e.g., incubated, in vitro with bone marrow or blood from apatient, e.g., a human.

In one embodiment, a column containing an anti-PRAME antibody bound to asolid matrix is used to remove advanced phase hematopoetic stem cellsand/or immature myeloid cells from a bone marrow or blood sample.

The anti-PRAME antibodies used in the in vitro depletion of advancedphase CML hematopoetic stem cells and/or immature myeloid cells fromsamples can be conjugated to detectable labels (e.g., various enzymes,fluorescent materials, luminescent materials, bioluminescent materials,and radioactive materials) or therapeutic agents (e.g., cytostatic andcytocidal agents), which are disclosed in section 5.8.3.

Anti-PRAME antibodies conjugated to detectable substances can beutilized to sort advanced phase hematopoetic stem cells and/or immaturemyeloid cells from bone marrow or peripheral blood samples by methodsknown to those of skill in the art. In one embodiment, advanced phasehematopoetic stem cells and/or immature myeloid cells are sorted using afluorescence activated cell sorter (FACS). Fluorescence activated cellsorting (FACS) is a well-known method for separating particles,including cells, based on the fluorescent properties of the particles(Kamarch, 1987, Methods Enzymol, 151:150-165). Laser excitation offluorescent moieties in the individual particles results in a smallelectrical charge allowing electromagnetic separation of positive andnegative particles from a mixture.

In one embodiment, bone marrow or peripheral blood samples, obtainedfrom a patient, e.g., a human, are incubated with fluorescently labeledPRAME specific antibodies for a time sufficient to allow the labeledantibodies to bind to the cells. In an alternative embodiment, suchcells are incubated with PRAME specific antibodies, the cells arewashed, and the cells are incubated with a second labeled antibody thatrecognizes the PRAME specific antibodies. In accordance with theseembodiments, the cells are washed and processed through the cell sorter,allowing separation of cells that bind both antibodies to be separatedfrom hybrid cells that do not bind both antibodies. FACS sortedparticles may be directly deposited into individual wells of 96-well or384-well plates to facilitate separation.

In another embodiment, magnetic beads can be used to separate advancedphase immature myeloid cells from bone marrow or peripheral bloodsamples. Advanced phase immature myeloid cells may be sorted using amagnetic activated cell sorting (MACS) technique, a method forseparating particles based on their ability to bind magnetic beads(0.5-100 nm diameter) (Dynal, 1995). A variety of useful modificationscan be performed on the magnetic microspheres, including covalentaddition of antibody which immunospecifically recognizes PRAME. Amagnetic field is then applied, to physically manipulate the selectedbeads. The beads are then mixed with the cells to allow binding. Cellsare then passed through a magnetic field to separate out advanced phaseCML hematopoetic stem cells and/or immature myeloid cells.

Bone marrow or peripheral blood sample from a patient that is depletedof advanced phase CML hematopoetic stem cells and/or immature myeloidcells can be used for autologous transplant treatment of the patient.Healthy bone marrow or peripheral blood cells from a sample depleted ofadvanced phase CML hematopoetic stem cells and/or immature myeloid cellscan be collected. These cells can then be administered to the patient toreplace the abnormal cells in the patient's bone marrow. Healthy bonemarrow or peripheral blood cells can also be stored, e.g., frozen, fortransplant at a later time.

5.5. Methods for Screening Agents that Modulate CML Progression/Targetor IM Resistance Proteins

Agents that modulate the expression or activity of a CMLprogression/target gene or encoded protein (or imatinib resistance geneor encoded protein), or modulate interaction of a CML progression/targetprotein (or imatinib resistance protein) with other proteins ormolecules can be identified using a method described in this section.Such agents are useful in treating CML patients who exhibit aberrantregulation of these genes. In the following, for simplicity, methodsdirected to CML progression/target gene are described. These methods areequally applicable to imatinib resistance genes.

5.5.1. Screening Assays

The following assays are designed to identify compounds that bind to aCML progression gene or its products, bind to other cellular proteinsthat interact with a CML progression protein, bind to cellularconstituents, e.g., proteins, that are affected by a CML progressionprotein, or bind to compounds that interfere with the interaction of theCML progression gene or its product with other cellular proteins and tocompounds which modulate the expression or activity of a CML progressiongene (i.e., modulate the expression level of the CML progression geneand/or modulate the activity level of the CML progression protein).Assays may additionally be utilized which identify compounds which bindto CML progression protein regulatory sequences (e.g., promotersequences), see e.g., Platt, K. A., 1994, J. Biol. Chem.269:28558-28562, which is incorporated herein by reference in itsentirety, which may modulate the level of CML progression geneexpression. Compounds may include, but are not limited to, small organicmolecules which are able to affect expression of the CML progressiongene or some other gene involved in the CML progression proteinpathways, or other cellular proteins. Further, among these compounds arecompounds which affect the level of CML progression gene expressionand/or CML progression protein activity and which can be used in theregulation of sensitivity to the effect of a chemotherapy agent.

Compounds may include, but are not limited to, peptides such as, forexample, soluble peptides, including but not limited to, Ig-tailedfusion peptides, and members of random peptide libraries (see, e.g.,Lam, K. S. et al., 1991, Nature 354:82-84; Houghten, R. et al., 1991,Nature 354:84-86), and combinatorial chemistry-derived molecular librarymade of D- and/or L-configuration amino acids, phosphopeptides(including, but not limited to members of random or partiallydegenerate, directed phosphopeptide libraries; see, e.g., Songyang, Z.et al., 1993, Cell 72:767-778), antibodies (including, but not limitedto, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric orsingle chain antibodies, and Fab, F(ab′)₂ and Fab expression libraryfragments, and epitope-binding fragments thereof), and small organic orinorganic molecules.

Compounds identified via assays such as those described herein may beuseful, for example, in modulating the biological function of the CMLprogression protein.

In vitro systems may be designed to identify compounds capable ofbinding a CML progression protein. Compounds identified may be useful,for example, in modulating the activity of wild type and/or mutant CMLprogression protein, may be useful in elaborating the biologicalfunction of the CML progression protein, may be utilized in screens foridentifying compounds that disrupt normal CML progression proteininteractions, or may in themselves disrupt such interactions.

The principle of the assays used to identify compounds that bind to theCML progression protein involves preparing a reaction mixture of the CMLprogression protein and the test compound under conditions and for atime sufficient to allow the two components to interact and bind, thusforming a complex which can be removed and/or detected in the reactionmixture. These assays can be conducted in a variety of ways. Forexample, one method to conduct such an assay would involve anchoring CMLprogression protein or the test substance onto a solid phase anddetecting CML progression protein/test compound complexes anchored onthe solid phase at the end of the reaction. In one embodiment of such amethod, the CML progression protein may be anchored onto a solidsurface, and the test compound, which is not anchored, may be labeled,either directly or indirectly.

In practice, microtiter plates may conveniently be utilized as the solidphase. The anchored component may be immobilized by non-covalent orcovalent attachments. Non-covalent attachment may be accomplished bysimply coating the solid surface with a solution of the protein anddrying. Alternatively, an immobilized antibody, preferably a monoclonalantibody, specific for the protein to be immobilized may be used toanchor the protein to the solid surface. The surfaces may be prepared inadvance and stored.

In order to conduct the assay, the nonimmobilized component is added tothe coated surface containing the anchored component. After the reactionis complete, unreacted components are removed (e.g., by washing) underconditions such that any complexes formed will remain immobilized on thesolid surface. The detection of complexes anchored on the solid surfacecan be accomplished in a number of ways. Where the previouslynonimmobilized component is pre-labeled, the detection of labelimmobilized on the surface indicates that complexes were formed. Wherethe previously nonimmobilized component is not pre-labeled, an indirectlabel can be used to detect complexes anchored on the surface; e.g.,using a labeled antibody specific for the previously nonimmobilizedcomponent (the antibody, in turn, may be directly labeled or indirectlylabeled with a labeled anti-Ig antibody).

Alternatively, a reaction can be conducted in a liquid phase, thereaction products separated from unreacted components, and complexesdetected; e.g., using an immobilized antibody specific for a CMLprogression protein or the test compound to anchor any complexes formedin solution, and a labeled antibody specific for the other component ofthe possible complex to detect anchored complexes.

The CML progression gene or CML progression protein may interact in vivowith one or more intracellular or extracellular molecules, such asproteins. For purposes of this discussion, such molecules are referredto herein as “binding partners”. Compounds that disrupt CML progressionprotein binding may be useful in modulating the activity of the CMLprogression protein. Compounds that disrupt CML progression gene bindingmay be useful in modulating the expression of the CML progression gene,such as by modulating the binding of a regulator of CML progressiongene. Such compounds may include, but are not limited to molecules suchas peptides which would be capable of gaining access to the CMLprogression protein.

The basic principle of the assay systems used to identify compounds thatinterfere with the interaction between the CML progression protein andits intracellular or extracellular binding partner or partners involvespreparing a reaction mixture containing the CML progression protein, andthe binding partner under conditions and for a time sufficient to allowthe two to interact and bind, thus forming a complex. In order to test acompound for inhibitory activity, the reaction mixture is prepared inthe presence and absence of the test compound. The test compound may beinitially included in the reaction mixture, or may be added at a timesubsequent to the addition of a CML progression protein and its bindingpartner. Control reaction mixtures are incubated without the testcompound or with a placebo. The formation of any complexes between theCML progression protein and the binding partner is then detected. Theformation of a complex in the control reaction, but not in the reactionmixture containing the test compound, indicates that the compoundinterferes with the interaction of the CML progression protein and theinteractive binding partner. Additionally, complex formation withinreaction mixtures containing the test compound and a normal CMLprogression protein may also be compared to complex formation withinreaction mixtures containing the test compound and a mutant CMLprogression protein. This comparison may be important in those caseswhere it is desirable to identify compounds that disrupt interactions ofmutant but not the normal CML progression protein.

The assay for compounds that interfere with the interaction of the CMLprogression proteins and binding partners can be conducted in aheterogeneous or homogeneous format. Heterogeneous assays involveanchoring either the CML progression protein or the binding partner ontoa solid phase and detecting complexes anchored on the solid phase at theend of the reaction. In homogeneous assays, the entire reaction iscarried out in a liquid phase. In either approach, the order of additionof reactants can be varied to obtain different information about thecompounds being tested. For example, test compounds that interfere withthe interaction between the CML progression proteins and the bindingpartners, e.g., by competition, can be identified by conducting thereaction in the presence of the test substance; i.e., by adding the testsubstance to the reaction mixture prior to or simultaneously with theCML progression protein and interactive binding partner. Alternatively,test compounds that disrupt preformed complexes, e.g. compounds withhigher binding constants that displace one of the components from thecomplex, can be tested by adding the test compound to the reactionmixture after complexes have been formed. The various formats aredescribed briefly below.

In a heterogeneous assay system, either the CML progression protein orits interactive binding partner, is anchored onto a solid surface, whilethe non-anchored species is labeled, either directly or indirectly. Inpractice, microtiter plates are conveniently utilized. The anchoredspecies may be immobilized by non-covalent or covalent attachments.Non-covalent attachment may be accomplished simply by coating the solidsurface with a solution of the CML progression protein or bindingpartner and drying. Alternatively, an immobilized antibody specific forthe species to be anchored may be used to anchor the species to thesolid surface. The surfaces may be prepared in advance and stored.

In order to conduct the assay, the partner of the immobilized species isexposed to the coated surface with or without the test compound. Afterthe reaction is complete, unreacted components are removed (e.g., bywashing) and any complexes formed will remain immobilized on the solidsurface. The detection of complexes anchored on the solid surface can beaccomplished in a number of ways. Where the non-immobilized species ispre-labeled, the detection of label immobilized on the surface indicatesthat complexes were formed. Where the non-immobilized species is notpre-labeled, an indirect label can be used to detect complexes anchoredon the surface; e.g., using a labeled antibody specific for theinitially non-immobilized species (the antibody, in turn, may bedirectly labeled or indirectly labeled with a labeled anti-Ig antibody).Depending upon the order of addition of reaction components, testcompounds which inhibit complex formation or which disrupt preformedcomplexes can be detected.

Alternatively, the reaction can be conducted in a liquid phase in thepresence or absence of the test compound, the reaction productsseparated from unreacted components, and complexes detected; e.g., usingan immobilized antibody specific for one of the binding components toanchor any complexes formed in solution, and a labeled antibody specificfor the other partner to detect anchored complexes. Again, dependingupon the order of addition of reactants to the liquid phase, testcompounds which inhibit complex or which disrupt preformed complexes canbe identified.

In an alternative embodiment of the invention, a homogeneous assay canbe used. In this approach, a preformed complex of the CML progressionprotein and the interactive binding partner is prepared in which eitherthe CML progression protein or its binding partners is labeled, but thesignal generated by the label is quenched due to complex formation (see,e.g., U.S. Pat. No. 4,109,496 which utilizes this approach forimmunoassays). The addition of a test substance that competes with anddisplaces one of the species from the preformed complex will result inthe generation of a signal above background. In this way, testsubstances which disrupt CML progression protein/binding partnerinteraction can be identified.

In a particular embodiment, the CML progression protein can be preparedfor immobilization using recombinant DNA techniques. For example, thecoding region of CML progression gene can be fused to aglutathione-S-transferase (GST) gene using a fusion vector, such aspGEX-5X-1, in such a manner that its binding activity is maintained inthe resulting fusion protein. The interactive binding partner can bepurified and used to raise a monoclonal antibody, using methodsroutinely practiced in the art. This antibody can be labeled with theradioactive isotope ¹²⁵I, for example, by methods routinely practiced inthe art. In a heterogeneous assay, e.g., the GST-CML progression proteinfusion protein can be anchored to glutathione-agarose beads. Theinteractive binding partner can then be added in the presence or absenceof the test compound in a manner that allows interaction and binding tooccur. At the end of the reaction period, unbound material can be washedaway, and the labeled monoclonal antibody can be added to the system andallowed to bind to the complexed components. The interaction between theCML progression protein and the interactive binding partner can bedetected by measuring the amount of radioactivity that remainsassociated with the glutathione-agarose beads. A successful inhibitionof the interaction by the test compound will result in a decrease inmeasured radioactivity.

Alternatively, the GST-CML progression protein fusion protein and theinteractive binding partner can be mixed together in liquid in theabsence of the solid glutathione-agarose beads. The test compound can beadded either during or after the species are allowed to interact. Thismixture can then be added to the glutathione-agarose beads and unboundmaterial is washed away. Again the extent of inhibition of the CMLprogression protein/binding partner interaction can be detected byadding the labeled antibody and measuring the radioactivity associatedwith the beads.

In another embodiment of the invention, these same techniques can beemployed using peptide fragments that correspond to the binding domainsof the CML progression protein and/or the interactive binding partner(in cases where the binding partner is a protein), in place of one orboth of the full length proteins. Any number of methods routinelypracticed in the art can be used to identify and isolate the bindingsites. These methods include, but are not limited to, mutagenesis of thegene encoding one of the proteins and screening for disruption ofbinding in a co-immunoprecipitation assay. Compensating mutations in thegene encoding the second species in the complex can then be selected.Sequence analysis of the genes encoding the respective proteins willreveal the mutations that correspond to the region of the proteininvolved in interactive binding. Alternatively, one protein can beanchored to a solid surface using methods described in this sectionabove, and allowed to interact with and bind to its labeled bindingpartner, which has been treated with a proteolytic enzyme, such astrypsin. After washing, a short, labeled peptide comprising the bindingdomain may remain associated with the solid material, which can beisolated and identified by amino acid sequencing. Also, once the genecoding for the binding partner is obtained, short gene segments can beengineered to express peptide fragments of the protein, which can thenbe tested for binding activity and purified or synthesized.

For example, and not by way of limitation, a CML progression protein canbe anchored to a solid material as described in this section, above, bymaking a GST-CML progression protein fusion protein and allowing it tobind to glutathione agarose beads. The interactive binding partner canbe labeled with a radioactive isotope, such as ³⁵S, and cleaved with aproteolytic enzyme such as trypsin. Cleavage products can then be addedto the anchored GST-CML progression protein fusion protein and allowedto bind. After washing away unbound peptides, labeled bound material,representing the binding partner binding domain, can be eluted,purified, and analyzed for amino acid sequence by well-known methods.Peptides so identified can be produced synthetically or fused toappropriate facilitative proteins using recombinant DNA technology.

Some CML progression proteins are kinases. Kinase activity of a CMLprogression protein can be assayed in vitro using a synthetic peptidesubstrate of a CML progression protein of interest, e.g., a GSK-derivedbiotinylated peptide substrate. The phosphopeptide product isquantitated using a Homogenous Time-Resolved Fluorescence (HTRF) assaysystem (Park et al., 1999, Anal. Biochem. 269:94-104). The reactionmixture contains suitable amounts of ATP, peptide substrate, and the CMLprogression protein. The peptide substrate has a suitable amino acidsequence and is biotinylated at the N-terminus. The kinase reaction isincubated, and then terminated with Stop/Detection Buffer and GSK3 ccanti-phosphoserine antibody (e.g., Cell Signaling Technologies, Beverly,Mass.; Cat#9338) labeled with europium-chelate (e.g., from Perkin Elmer,Boston, Mass.). The reaction is allowed to equilibrate, and relativefluorescent units are determined Inhibitor compounds are assayed in thereaction described above, to determine compound IC50s. A particularcompound is added to in a half-log dilution series covering a suitablerange of concentrations, e.g., from 1 nM to 100 μM. Relative phosphosubstrate formation, read as HTRF fluorescence units, is measured overthe range of compound concentrations and a titration curve generatedusing a four parameter sigmoidal fit. Specific compounds having IC₅₀below a predetermined threshold value, e.g., ≦50 μM against a substrate,can be identified.

The extent of peptide phosphorylation can be determined by HomogeneousTime Resolved Fluorescence (HTRF) using a lanthanide chelate(Lance)-coupled monoclonal antibody specific for the phosphopeptide incombination with a streptavidin-linked allophycocyanin (SA-APC)fluorophore which binds to the biotin moiety on the peptide. When theLance and APC are in proximity (i.e. bound to the same phosphopeptidemolecule), a non-radiative energy transfer takes place from the Lance tothe APC, followed by emission of light from APC at 665 nm. The assay canbe run using various assay format, e.g., streptavidin flash plate assay,streptavidin filter plate assay.

A standard PKA assay can be used to assay the activity of protein kinaseA (PKA). A standard PKC assay can be used to assay the activity ofprotein kinase C(PKC). The most common methods for assaying PKA or PKCactivity involves measuring the transfer of ³²P-labeled phosphate to aprotein or peptide substrate that can be captured on phosphocellulosefilters via weak electrostatic interactions.

Kinase inhibitors can be identified using fluorescence polarization tomonitor kinase activity. This assay utilizes GST-CML progressionprotein, peptide substrate, peptide substrate tracer, an anti-phosphomonoclonal IgG, and the inhibitor compound. Reactions are incubated fora period of time and then terminated. Stopped reactions are incubatedand fluorescence polarization values determined.

In a specific embodiment, a standard SPA Filtration Assay andFlashPlate® Kinase Assay can be used to measure the activity of a CMLprogression protein. In these assays, GST-CML progression protein,biotinylated peptide substrate, ATP, and ³³P-γ-ATP are allowed to react.After a suitable period of incubation, the reactions are terminated. Ina SPA Filtration Assay, peptide substrate is allowed to bindScintilation proximity assay (SPA) beads (Amersham Biosciences),followed by filtration on a Packard GF/B Unifilter plate and washed withphosphate buffered saline. Dried plates are sealed and the amount of ³³Pincorporated into the peptide substrate is determined. In a FlashPlate®Kinase Assay, a suitable amount of the reaction is transferred tostreptavidin-coated FlashPlates® (NEN) and incubated. Plates are washed,dried, sealed and the amount of ³³P incorporated into the peptidesubstrate is determined

A standard DELFIA® Kinase Assay can also be used. In a DELFIA® KinaseAssay, GST-CML progression protein, peptide substrate, and ATP areallowed to react. After the reactions are terminated, the biotin-peptidesubstrates are captured in the stopped reactions. Wells are washed andreacted with anti-phospho polyclonal antibody and europium labeledanti-rabbit-IgG. Wells are washed and europium released from the boundantibody is detected.

Other assays, such as those described in WO 04/080973, WO 02/070494, andWO 03/101444, may also be utilized to determine biological activity ofthe instant compounds.

5.5.2. Screening Compounds that Modulate Expression or Activity of aGene and/or its Products

For CML progression genes that are kinases, inhibitor compounds can beassayed for their ability to inhibit a CML progression protein inhematopoetic stem cells and/or immature myeloid cells by monitoring thephosphorylation or autophosphorylation in response to the compound.Cells are grown in culture medium. Cells are pooled, counted, seededinto 6 well dishes at 200,000 cells per well in 2 ml media, andincubated. Serial dilution series of compounds or control are added toeach well and incubated. Following the incubation period, each well iswashed and Protease Inhibitor Cocktail Complete is added to each well.Lysates are then transferred to microcentrifuge tubes and frozen at −80°C. Lysates are thawed on ice and cleared by centrifugation and thesupernatants are transferred to clean tubes. Samples are electorphoresedand proteins are transferred onto PVDF. Blots are then blocked andprobed using an antibody against phospho-serine or phospho threonine.Bound antibody is visualized using a horseradish peroxidase conjugatedsecondary antibody and enhanced chemiluminescence. After stripping ofthe first antibody set, blots are re-probed for total CML progressionprotein, using a monoclonal antibody specific for the CML progressionprotein. The CML progression protein monoclonal is detected using asheep anti-mouse IgG coupled to horseradish peroxidase and enhancedchemiluminescence. ECL exposed films are scanned and the intensity ofspecific bands is quantitated. Titrations are evaluated for level ofphosphor-Ser signal normalized to total CML progression protein and IC50values are calculated.

Detection of phosphonucleolin in cell lysates can be carried out usingbiotinylated anti-nucleolin antibody and ruthenylated goat anti-mouseantibody. To each well of a 96-well plate is added biotynylatedanti-nucleolin antibody and streptavidin coated paramagnetic beads,along with a suitable cell lysate. The antibodies and lysate areincubated. Next, another anti-phosphonucleolin antibody are added toeach well of the lysate mix and incubated. Lastly, the ruthenylated goatanti-mouse antibody in antibody buffer is added to each well andincubated. The lysate antibody mixtures are read and EC50s for compounddependent increases in phosphor-nucleolin are determined.

The compounds identified in the screen include compounds thatdemonstrate the ability to selectively modulate the expression oractivity of a CML progression gene or its encoded protein. Thesecompounds include but are not limited to siRNA, antisense nucleic acid,ribozyme, triple helix forming nucleic acid, antibody, and polypeptidemolecules, aptamers, and small organic or inorganic molecules.

5.6. Methods of Performing RNA Interference

Any method known in the art for gene silencing can be used in thepresent invention (see, e.g., Guo et al., 1995, Cell 81:611-620; Fire etal., 1998, Nature 391:806-811; Grant, 1999, Cell 96:303-306; Tabara etal., 1999, Cell 99:123-132; Zamore et al., 2000, Cell 101:25-33; Bass,2000, Cell 101:235-238; Petcherski et al., 2000, Nature 405:364-368;Elbashir et al., Nature 411:494-498; Paddison et al., Proc. Natl. Acad.Sci. USA 99:1443-1448). The siRNAs targeting a gene can be designedaccording to methods known in the art (see, e.g., InternationalApplication Publication No. WO 2005/018534, published on Mar. 3, 2005,and Elbashir et al., 2002, Methods 26:199-213, each of which isincorporated herein by reference in its entirety).

An siRNA having only partial sequence homology to a target gene can alsobe used (see, e.g., International Application Publication No. WO2005/018534, published on Mar. 3, 2005, which is incorporated herein byreference in its entirety). In one embodiment, an siRNA that comprises asense strand contiguous nucleotide sequence of 11-18 nucleotides that isidentical to a sequence of a transcript of a gene but the siRNA does nothave full length homology to any sequences in the transcript is used tosilence the gene. Preferably, the contiguous nucleotide sequence is inthe central region of the siRNA molecules. A contiguous nucleotidesequence in the central region of an siRNA can be any continuous stretchof nucleotide sequence in the siRNA which does not begin at the 3′ end.For example, a contiguous nucleotide sequence of 11 nucleotides can bethe nucleotide sequence 2-12, 3-13, 4-14, 5-15, 6-16, 7-17, 8-18, or9-19. In preferred embodiments, the contiguous nucleotide sequence is11-16, 11-15, 14-15, 11, 12, or 13 nucleotides in length.

In another embodiment, an siRNA that comprises a 3′ sense strandcontiguous nucleotide sequence of 9-18 nucleotides which is identical toa sequence of a transcript of a gene but which siRNA does not have fulllength sequence identity to any contiguous sequences in the transcriptis used to silence the gene. In this application, a 3′ 9-18 nucleotidesequence is a continuous stretch of nucleotides that begins at the firstpaired base, i.e., it does not comprise the two base 3′ overhang. Thus,when it is stated that a particular nucleotide sequence is at the 3′ endof the siRNA, the 2 base overhang is not considered. In preferredembodiments, the contiguous nucleotide sequence is 9-16, 9-15, 9-12, 11,10, or 9 nucleotides in length.

An siRNA having only partial sequence homology to its target genes isespecially useful for silencing a plurality of different genes in acell. In one embodiment, an siRNA is used to silence a plurality ofdifferent genes, the transcript of each of the genes comprises anucleotide sequence that is identical to a central contiguous nucleotidesequence of at least 11 nucleotides of the sense strand or the antisensestrand of the siRNA, and/or comprises a nucleotide sequence that isidentical to a contiguous nucleotide sequence of at least 9 nucleotidesat the 3′ end of the sense strand or the antisense strand of the siRNA.In preferred embodiments, the central contiguous nucleotide sequence is11-15, 14-15, 11, 12, or 13 nucleotides in length. In other preferredembodiments, the 3′ contiguous nucleotide sequence is 9-15, 9-12, 11,10, or 9 nucleotides in length.

In one embodiment, in vitro siRNA transfection is carried out asfollows: one day prior to transfection, 100 microliters of chosen cells,e.g., cervical cancer HeLa cells (ATCC, Cat. No. CCL-2), grown inDMEM/10% fetal bovine serum (Invitrogen, Carlsbad, Calif.) toapproximately 90% confluency are seeded in a 96-well tissue cultureplate (Corning, Corning, N.Y.) at 1500 cells/well. For each transfection85 microliters of OptiMEM (Invitrogen) is mixed with 5 microliter ofserially diluted siRNA (Dharma on, Denver) from a 20 micro molar stock.For each transfection 5 microliter OptiMEM is mixed with 5 microliterOligofectamine reagent (Invitrogen) and incubated 5 minutes at roomtemperature. The 10 microliter OptiMEM/Oligofectamine mixture isdispensed into each tube with the OptiMEM/siRNA mixture, mixed andincubated 15-20 minutes at room temperature. 10 microliter of thetransfection mixture is aliquoted into each well of the 96-well plateand incubated for 4 hours at 37° C. and 5% CO₂.

In preferred embodiments, an siRNA pool containing at least k (k=2, 3,4, 5, 6 or 10) different siRNAs targeting the secondary target gene atdifferent sequence regions is used to transfect the cells. In anotherpreferred embodiment, an siRNA pool containing at least k (k=2, 3, 4, 5,6 or 10) different siRNAs targeting two or more different target genesis used to transfect the cells.

In a preferred embodiment, the total siRNA concentration of the pool isabout the same as the concentration of a single siRNA when usedindividually, e.g., 100 nM. Preferably, the total concentration of thepool of siRNAs is an optimal concentration for silencing the intendedtarget gene. An optimal concentration is a concentration furtherincrease of which does not increase the level of silencingsubstantially. In one embodiment, the optimal concentration is aconcentration further increase of which does not increase the level ofsilencing by more than 5%, 10% or 20%. In a preferred embodiment, thecomposition of the pool, including the number of different siRNAs in thepool and the concentration of each different siRNA, is chosen such thatthe pool of siRNAs causes less than 30%, 20%, 10% or 5%, 1%, 0.1% or0.01% of silencing of any off-target genes (e.g., as determined bystandard nucleic acid assay, e.g., PCR). In another preferredembodiment, the concentration of each different siRNA in the pool ofdifferent siRNAs is about the same. In still another preferredembodiment, the respective concentrations of different siRNAs in thepool are different from each other by less than 5%, 10%, 20% or 50% ofthe concentration of any one siRNA or said total siRNA concentration ofsaid different siRNAs. In still another preferred embodiment, at leastone siRNA in the pool of different siRNAs constitutes more than 90%,80%, 70%, 50%, or 20% of the total siRNA concentration in the pool. Instill another preferred embodiment, none of the siRNAs in the pool ofdifferent siRNAs constitutes more than 90%, 80%, 70%, 50%, or 20% of thetotal siRNA concentration in the pool. In other embodiments, each siRNAin the pool has an concentration that is lower than the optimalconcentration when used individually. In a preferred embodiment, eachdifferent siRNA in the pool has an concentration that is lower than theconcentration of the siRNA that is effective to achieve at least 30%,50%, 75%, 80%, 85%, 90% or 95% silencing when used in the absence ofother siRNAs or in the absence of other siRNAs designed to silence thegene. In another preferred embodiment, each different siRNA in the poolhas a concentration that causes less than 30%, 20%, 10% or 5% ofsilencing of the gene when used in the absence of other siRNAs or in theabsence of other siRNAs designed to silence the gene. In a preferredembodiment, each siRNA has a concentration that causes less than 30%,20%, 10% or 5% of silencing of the target gene when used alone, whilethe plurality of siRNAs causes at least 80% or 90% of silencing of thetarget gene.

Another method for gene silencing is to introduce an shRNA, for shorthairpin RNA (see, e.g., Paddison et al., 2002, Genes Dev. 16, 948-958;Brummelkamp et al., 2002, Science 296, 550-553; Sui, G. et al. 2002,Proc. Natl. Acad. Sci. USA 99, 5515-5520, all of which are incorporatedby reference herein in their entirety), which can be processed in thecells into siRNA. In this method, a desired siRNA sequence is expressedfrom a plasmid (or virus) as an inverted repeat with an intervening loopsequence to form a hairpin structure. The resulting RNA transcriptcontaining the hairpin is subsequently processed by Dicer to producesiRNAs for silencing. Plasmid-based shRNAs can be expressed stably incells, allowing long-term gene silencing in cells both in vitro and invivo, e.g., in animals (see, McCaffrey et al. 2002, Nature 418, 38-39;Xia et al., 2002, Nat. Biotech. 20, 1006-1010; Lewis et al., 2002, Nat.Genetics 32, 107-108; Rubinson et al., 2003, Nat. Genetics 33, 401-406;Tiscornia et al., 2003, Proc. Natl. Acad. Sci. USA 100, 1844-1848, allof which are incorporated by reference herein in their entirety). Thus,in one embodiment, a plasmid-based shRNA is used.

In a preferred embodiment, shRNAs are expressed from recombinant vectorsintroduced either transiently or stably integrated into the genome (see,e.g., Paddison et al., 2002, Genes Dev 16:948-958; Sui et al., 2002,Proc Natl Acad Sci USA 99:5515-5520; Yu et al., 2002, Proc Natl Acad SciUSA 99:6047-6052; Miyagishi et al., 2002, Nat Biotechnol 20:497-500;Paul et al., 2002, Nat Biotechnol 20:505-508; Kwak et al., 2003, JPharmacol Sci 93:214-217; Brummelkamp et al., 2002, Science 296:550-553;Boden et al., 2003, Nucleic Acids Res 31:5033-5038; Kawasaki et al.,2003, Nucleic Acids Res 31:700-707). The siRNA that disrupts the targetgene can be expressed (via an shRNA) by any suitable vector whichencodes the shRNA. The vector can also encode a marker which can be usedfor selecting clones in which the vector or a sufficient portion thereofis integrated in the host genome such that the shRNA is expressed. Anystandard method known in the art can be used to deliver the vector intothe cells. In one embodiment, cells expressing the shRNA are generatedby transfecting suitable cells with a plasmid containing the vector.Cells can then be selected by the appropriate marker. Clones are thenpicked, and tested for knockdown. In a preferred embodiment, theexpression of the shRNA is under the control of an inducible promotersuch that the silencing of its target gene can be turned on whendesired. Inducible expression of an siRNA is particularly useful fortargeting essential genes.

In one embodiment, the expression of the shRNA is under the control of aregulated promoter that allows tuning of the silencing level of thetarget gene. This allows screening against cells in which the targetgene is partially knocked out. As used herein, a “regulated promoter”refers to a promoter that can be activated when an appropriate inducingagent is present. An “inducing agent” can be any molecule that can beused to activate transcription by activating the regulated promoter. Aninducing agent can be, but is not limited to, a peptide or polypeptide,a hormone, or an organic small molecule. An analogue of an inducingagent, i.e., a molecule that activates the regulated promoter as theinducing agent does, can also be used. The level of activity of theregulated promoter induced by different analogues may be different, thusallowing more flexibility in tuning the activity level of the regulatedpromoter. The regulated promoter in the vector can be any mammaliantranscription regulation system known in the art (see, e.g., Gossen etal, 1995, Science 268:1766-1769; Lucas et al, 1992, Annu. Rev. Biochem.61:1131; Li et al., 1996, Cell 85:319-329; Saez et al., 2000, Proc.Natl. Acad. Sci. USA 97:14512-14517; and Pollock et al., 2000, Proc.Natl. Acad. Sci. USA 97:13221-13226). In preferred embodiments, theregulated promoter is regulated in a dosage and/or analogue dependentmanner. In one embodiment, the level of activity of the regulatedpromoter is tuned to a desired level by a method comprising adjustingthe concentration of the inducing agent to which the regulated promoteris responsive. The desired level of activity of the regulated promoter,as obtained by applying a particular concentration of the inducingagent, can be determined based on the desired silencing level of thetarget gene.

In one embodiment, a tetracycline regulated gene expression system isused (see, e.g., Gossen et al, 1995, Science 268:1766-1769; U.S. Pat.No. 6,004,941). A tet regulated system utilizes components of the tetrepressor/operator/inducer system of prokaryotes to regulate geneexpression in eukaryotic cells. Thus, the invention provides methods forusing the tet regulatory system for regulating the expression of anshRNA linked to one or more tet operator sequences. The methods involveintroducing into a cell a vector encoding a fusion protein thatactivates transcription. The fusion protein comprises a firstpolypeptide that binds to a tet operator sequence in the presence oftetracycline or a tetracycline analogue operatively linked to a secondpolypeptide that activates transcription in cells. By modulating theconcentration of a tetracycline, or a tetracycline analogue, expressionof the tet operator-linked shRNA is regulated.

In other embodiments, an ecdyson regulated gene expression system (see,e.g., Saez et al., 2000, Proc. Natl. Acad. Sci. USA 97:14512-14517), oran MMTV glucocorticoid response element regulated gene expression system(see, e.g., Lucas et al, 1992, Annu. Rev. Biochem. 61:1131) may be usedto regulate the expression of the shRNA.

In one embodiment, the pRETRO-SUPER (pRS) vector which encodes apuromycin-resistance marker and drives shRNA expression from an H1 (RNAPol III) promoter is used. The pRS-shRNA plasmid can be generated by anystandard method known in the art. In one embodiment, the pRS-shRNA isdeconvoluted from the library plasmid pool for a chosen gene bytransforming bacteria with the pool and looking for clones containingonly the plasmid of interest. Preferably, a 19mer siRNA sequence is usedalong with suitable forward and reverse primers for sequence specificPCR. Plasmids are identified by sequence specific PCR, and confirmed bysequencing. Cells expressing the shRNA are generated by transfectingsuitable cells with the pRS-shRNA plasmid. Cells are selected by theappropriate marker, e.g., puromycin, and maintained until colonies areevident. Clones are then picked, and tested for knockdown. In anotherembodiment, an shRNA is expressed by a plasmid, e.g., a pRS-shRNA. Theknockdown by the pRS-shRNA plasmid, can be achieved by transfectingcells using Lipofectamine 2000 (Invitrogen).

In yet another method, siRNAs can be delivered to an organ or tissue inan animal, such a human, in vivo (see, e.g., Song et al. 2003, Nat.Medicine 9, 347-351; Sorensen et al., 2003, J. Mol. Biol. 327, 761-766;Lewis et al., 2002, Nat. Genetics 32, 107-108, all of which areincorporated by reference herein in their entirety). In this method, asolution of siRNA is injected intravenously into the animal. The siRNAcan then reach an organ or tissue of interest and effectively reduce theexpression of the target gene in the organ or tissue of the animal.

5.7. Production of CML Progression/Target or IM Resistance Proteins andPeptides

CML progression proteins, or peptide fragments thereof, can be preparedfor uses according to the present invention. For example, CMLprogression proteins, or peptide fragments thereof, can be used for thegeneration of antibodies, in diagnostic assays, for screening ofinhibitors, or for the identification of other cellular gene productsinvolved in the regulation of expression and/or activity of a CMLprogression gene.

The CML progression proteins or peptide fragments thereof, may beproduced by recombinant DNA technology using techniques well known inthe art. The amino acid sequences of the CML progression proteins arewell-known and can be obtained from, e.g., GenBank®. Methods which arewell known to those skilled in the art can be used to constructexpression vectors containing CML progression protein coding sequencesand appropriate transcriptional and translational control signals. Thesemethods include, for example, in vitro recombinant DNA techniques,synthetic techniques, and in vivo genetic recombination. See, forexample, the techniques described in Sambrook et al., 1989, supra, andAusubel et al., 1989, supra. Alternatively, RNA capable of encoding CMLprogression protein sequences may be chemically synthesized using, forexample, synthesizers. See, for example, the techniques described in“Oligonucleotide Synthesis”, 1984, Gait, M. J. ed., IRL Press, Oxford,which is incorporated herein by reference in its entirety.

A variety of host-expression vector systems may be utilized to expressthe CML progression gene coding sequences. Such host-expression systemsrepresent vehicles by which the coding sequences of interest may beproduced and subsequently purified, but also represent cells which may,when transformed or transfected with the appropriate nucleotide codingsequences, exhibit the CML progression protein in situ. These includebut are not limited to microorganisms such as bacteria (e.g., E. coli,B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNAor cosmid DNA expression vectors containing CML progression proteincoding sequences; yeast (e.g., Saccharomyces, Pichia) transformed withrecombinant yeast expression vectors containing the CML progressionprotein coding sequences; insect cell systems infected with recombinantvirus expression vectors (e.g., baculovirus) containing the CMLprogression protein coding sequences; plant cell systems infected withrecombinant virus expression vectors (e.g., cauliflower mosaic virus,CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmidexpression vectors (e.g., Ti plasmid) containing CML progression proteincoding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293,3T3, N2a) harboring recombinant expression constructs containingpromoters derived from the genome of mammalian cells (e.g.,metallothionein promoter) or from mammalian viruses (e.g., theadenovirus late promoter; the vaccinia virus 7.5K promoter).

In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the use intended for the CMLprogression protein being expressed. For example, when a large quantityof such a protein is to be produced, for the generation ofpharmaceutical compositions of CML progression protein protein or forraising antibodies to CML progression protein protein, for example,vectors which direct the expression of high levels of fusion proteinproducts that are readily purified may be desirable. Such vectorsinclude, but are not limited, to the E. coli expression vector pUR278(Ruther et al., 1983, EMBO J. 2:1791), in which the CML progressionprotein coding sequence may be ligated individually into the vector inframe with the lac Z coding region so that a fusion protein is produced;pIN vectors (Inouye & Inouye, 1985, Nucleic Acids Res. 13:3101-3109; VanHeeke & Schuster, 1989, J. Biol. Chem. 264:5503-5509); and the like.pGEX vectors may also be used to express foreign polypeptides as fusionproteins with glutathione S-transferase (GST). In general, such fusionproteins are soluble and can easily be purified from lysed cells byadsorption to glutathione-agarose beads followed by elution in thepresence of free glutathione. The pGEX vectors are designed to includethrombin or factor Xa protease cleavage sites so that the cloned targetgene product can be released from the GST moiety.

In an insect system, Autographa californica nuclear polyhedrosis virus(AcNPV) is used as a vector to express foreign genes. The virus grows inSpodoptera frugiperda cells. The CML progression gene coding sequencemay be cloned individually into non-essential regions (for example thepolyhedrin gene) of the virus and placed under control of an AcNPVpromoter (for example the polyhedrin promoter). Successful insertion ofCML progression gene coding sequence will result in inactivation of thepolyhedrin gene and production of non-occluded recombinant virus (i.e.,virus lacking the proteinaceous coat coded for by the polyhedrin gene).These recombinant viruses are then used to infect Spodoptera frugiperdacells in which the inserted gene is expressed. (E.g., see Smith et al.,1983, J. Virol. 46: 584; Smith, U.S. Pat. No. 4,215,051).

In mammalian host cells, a number of viral-based expression systems maybe utilized. In cases where an adenovirus is used as an expressionvector, the CML progression gene coding sequence of interest may beligated to an adenovirus transcription/translation control complex,e.g., the late promoter and tripartite leader sequence. This chimericgene may then be inserted in the adenovirus genome by in vitro or invivo recombination. Insertion in a non-essential region of the viralgenome (e.g., region E1 or E3) will result in a recombinant virus thatis viable and capable of expressing CML progression protein in infectedhosts. (E.g., See Logan & Shenk, 1984, Proc. Natl. Acad. Sci. USA81:3655-3659). Specific initiation signals may also be required forefficient translation of inserted CML progression protein codingsequences. These signals include the ATG initiation codon and adjacentsequences. In cases where an entire CML progression gene, including itsown initiation codon and adjacent sequences, is inserted into theappropriate expression vector, no additional translational controlsignals may be needed. However, in cases where only a portion of the CMLprogression gene coding sequence is inserted, exogenous translationalcontrol signals, including, perhaps, the ATG initiation codon, must beprovided. Furthermore, the initiation codon must be in phase with thereading frame of the desired coding sequence to ensure translation ofthe entire insert. These exogenous translational control signals andinitiation codons can be of a variety of origins, both natural andsynthetic. The efficiency of expression may be enhanced by the inclusionof appropriate transcription enhancer elements, transcriptionterminators, etc. (see Bittner et al., 1987, Methods in Enzymol.153:516-544).

In addition, a host cell strain may be chosen which modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavage) of protein products maybe important for the function of the protein. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed. To thisend, eukaryotic host cells which possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product may be used. Such mammalian hostcells include but are not limited to CHO, VERO, BHK, HeLa, COS, MDCK,293, 3T3, WI38.

For long-term, high-yield production of recombinant proteins, stableexpression is preferred. For example, cell lines which stably expressthe CML progression protein may be engineered. Rather than usingexpression vectors which contain viral origins of replication, hostcells can be transformed with DNA controlled by appropriate expressioncontrol elements (e.g., promoter, enhancer, sequences, transcriptionterminators, polyadenylation sites, etc.), and a selectable marker.Following the introduction of the foreign DNA, engineered cells may beallowed to grow for 1-2 days in an enriched media, and then are switchedto a selective media. The selectable marker in the recombinant plasmidconfers resistance to the selection and allows cells to stably integratethe plasmid into their chromosomes and grow to form foci which in turncan be cloned and expanded into cell lines. This method mayadvantageously be used to engineer cell lines which express the CMLprogression protein. Such engineered cell lines may be particularlyuseful in screening and evaluation of compounds that affect theendogenous activity of the CML progression protein.

In another embodiment, the expression characteristics of an endogenousgene (e.g., a CML progression gene) within a cell, cell line ormicroorganism may be modified by inserting a DNA regulatory elementheterologous to the endogenous gene of interest into the genome of acell, stable cell line or cloned microorganism such that the insertedregulatory element is operatively linked with the endogenous gene (e.g.,a CML progression gene) and controls, modulates, activates, or inhibitsthe endogenous gene. For example, endogenous CML progression genes whichare normally “transcriptionally silent”, i.e., a CML progression genewhich is normally not expressed, or is expressed only at very low levelsin a cell line or microorganism, may be activated by inserting aregulatory element which is capable of promoting the expression of thegene product in that cell line or microorganism. Alternatively,transcriptionally silent, endogenous CML progression genes may beactivated by insertion of a promiscuous regulatory element that worksacross cell types.

A heterologous regulatory element may be inserted into a stable cellline or cloned microorganism, such that it is operatively linked withand activates or inhibits expression of endogenous CML progressiongenes, using techniques, such as targeted homologous recombination,which are well known to those of skill in the art, and described e.g.,in Chappel, U.S. Pat. No. 5,272,071; PCT Publication No. WO 91/06667published May 16, 1991; Skoultchi, U.S. Pat. No. 5,981,214; and Treco etal U.S. Pat. No. 5,968,502 and PCT Publication No. WO 94/12650 publishedJun. 9, 1994. Alternatively, non-targeted, e.g. non-homologousrecombination techniques may be used which are well-known to those ofskill in the art and described, e.g., in PCT Publication No. WO 99/15650published Apr. 1, 1999.

CML progression gene activation (or inactivation) may also beaccomplished using designer transcription factors using techniques wellknown in the art. Briefly, a designer zinc finger protein transcriptionfactor (ZFP-TF) is made which is specific for a regulatory region of theCML progression gene to be activated or inactivated. A constructencoding this designer ZFP-TF is then provided to a host cell in whichthe CML progression gene is to be controlled. The construct directs theexpression of the designer ZFP-TF protein, which in turn specificallymodulates the expression of the endogenous CML progression gene. Thefollowing references relate to various aspects of this approach infurther detail: Wang & Pabo, 1999, Proc. Natl. Acad. Sci. USA 96, 9568;Berg, 1997, Nature Biotechnol. 15, 323; Greisman & Pabo, 1997, Science275, 657; Berg & Shi, 1996, Science 271, 1081; Rebar & Pabo, 1994,Science 263, 671; Rhodes & Klug, 1993, Scientific American 269, 56;Pavletich & Pabo, 1991, Science 252, 809; Liu et al., 2001, J. Biol.Chem. 276, 11323; Zhang et al., 2000, J. Biol. Chem. 275, 33850; Beerliet al., 2000, Proc. Natl. Acad. Sci. USA 97, 1495; Kang et al., 2000, J.Biol. Chem. 275, 8742; Beerli et al., 1998, Proc. Natl. Acad. Sci. USA95, 14628; Kim & Pabo, 1998, Proc. Natl. Acad. Sci. USA 95, 2812; Chooet al., 1997, J. Mol. Biol. 273, 525; Kim & Pabo, 1997, J. Biol. Chem.272, 29795; Liu et al, 1997, Proc. Natl. Acad. Sci. USA 94, 5525; Kim etal, 1997, Proc. Natl. Acad. Sci. USA 94, 3616; Kikyo et al., 2000,Science 289, 2360; Robertson & Wolffe, 2000, Nature Reviews 1, 11; andGregory, 2001, Curr. Opin. Genet. Devt. 11, 142.

A number of selection systems may be used, including but not limited tothe herpes simplex virus thymidine kinase (Wigler, et al., 1977, Cell11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska &Szybalski, 1962, Proc. Natl. Acad. Sci. USA 48:2026), and adeninephosphoribosyltransferase (Lowy, et al., 1980, Cell 22:817) genes can beemployed in tk⁻, hgprt⁻ or aprt⁻ cells, respectively. Also,antimetabolite resistance can be used as the basis of selection for thefollowing genes: dhfr, which confers resistance to methotrexate (Wigler,et al., 1980, Natl. Acad. Sci. USA 77:3567; O'Hare, et al., 1981, Proc.Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance tomycophenolic acid (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA78:2072); neo, which confers resistance to the aminoglycoside G-418(Colberre-Garapin, et al., 1981, J. Mol. Biol. 150:1); and hygro, whichconfers resistance to hygromycin (Santerre, et al., 1984, Gene 30:147).

Alternatively, any fusion protein may be readily purified by utilizingan antibody specific for the fusion protein being expressed. Forexample, a system described by Janknecht et al. allows for the readypurification of non-denatured fusion proteins expressed in human celllines (Janknecht, et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-8976). In this system, the gene of interest is subcloned into avaccinia recombination plasmid such that the gene's open reading frameis translationally fused to an amino-terminal tag consisting of sixhistidine residues. Extracts from cells infected with recombinantvaccinia virus are loaded onto Ni²⁺.nitriloacetic acid-agarose columnsand histidine-tagged proteins are selectively eluted withimidazole-containing buffers.

In a specific embodiment, recombinant human CML progression proteins canbe expressed as a fusion protein with glutathione S-transferase at theamino-terminus (GST-CML progression protein) using standard baculovirusvectors and a (Bac-to-Bac®) insect cell expression system purchased fromGIBCO™ Invitrogen. Recombinant protein expressed in insect cells can bepurified using glutathione sepharose (Amersham Biotech) using standardprocedures described by the manufacturer.

5.8. Production of Antibodies that Bind a CML Progression/Target or IMResistance Protein

CML progression protein or a fragment thereof can be used to raiseantibodies which bind CML progression protein. Such antibodies includebut are not limited to polyclonal, monoclonal, chimeric, single chain,Fab fragments, and an Fab expression library. In a preferred embodiment,anti CML progression protein C-terminal antibodies are raised using anappropriate C-terminal fragment of a CML progression protein, e.g., thekinase domain. Such antibodies bind the kinase domain of the CMLprogression protein. In another preferred embodiment, anti CMLprogression protein N-terminal antibodies are raised using anappropriate N-terminal fragment of a CML progression protein. TheN-terminal domain of a CML progression protein are less homologous toother kinases, and therefore offered a more specific target for aparticular CML progression protein.

5.8.1. Production of Monoclonal Antibodies Specific for a CMLProgression/Target or Im Resistance Protein

Antibodies can be prepared by immunizing a suitable subject with a CMLprogression protein or a fragment thereof as an immunogen. The antibodytiter in the immunized subject can be monitored over time by standardtechniques, such as with an enzyme linked immunosorbent assay (ELISA)using immobilized polypeptide. If desired, the antibody molecules can beisolated from the mammal (e.g., from the blood) and further purified bywell-known techniques, such as protein A chromatography to obtain theIgG fraction.

At an appropriate time after immunization, e.g., when the specificantibody titers are highest, antibody-producing cells can be obtainedfrom the subject and used to prepare monoclonal antibodies by standardtechniques, such as the hybridoma technique originally described byKohler and Milstein (1975, Nature 256:495-497), the human B cellhybridoma technique by Kozbor et al. (1983, Immunol. Today 4:72), theEBV-hybridoma technique by Cole et al. (1985, Monoclonal Antibodies andCancer Therapy, Alan R. Liss, Inc., pp. 77-96) or trioma techniques. Thetechnology for producing hybridomas is well known (see Current Protocolsin Immunology, 1994, John Wiley & Sons, Inc., New York, N.Y.). Hybridomacells producing a monoclonal antibody are detected by screening thehybridoma culture supernatants for antibodies that bind the polypeptideof interest, e.g., using a standard ELISA assay.

Monoclonal antibodies are obtained from a population of substantiallyhomogeneous antibodies, i.e., the individual antibodies comprising thepopulation are identical except for possible naturally occurringmutations that may be present in minor amounts. Thus, the modifier“monoclonal” indicates the character of the antibody as not being amixture of discrete antibodies. For example, the monoclonal antibodiesmay be made using the hybridoma method first described by Kohler et al.,1975, Nature, 256:495, or may be made by recombinant DNA methods (U.S.Pat. No. 4,816,567). The term “monoclonal antibody” as used herein alsoindicates that the antibody is an immunoglobulin.

In the hybridoma method of generating monoclonal antibodies, a mouse orother appropriate host animal, such as a hamster, is immunized ashereinabove described to elicit lymphocytes that produce or are capableof producing antibodies that will specifically bind to the protein usedfor immunization (see, e.g., U.S. Pat. No. 5,914,112, which isincorporated herein by reference in its entirety).

Alternatively, lymphocytes may be immunized in vitro. Lymphocytes thenare fused with myeloma cells using a suitable fusing agent, such aspolyethylene glycol, to form a hybridoma cell (Goding, MonoclonalAntibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)).The hybridoma cells thus prepared are seeded and grown in a suitableculture medium that preferably contains one or more substances thatinhibit the growth or survival of the unfused, parental myeloma cells.For example, if the parental myeloma cells lack the enzyme hypoxanthineguanine phosphoribosyl transferase (HGPRT or HPRT), the culture mediumfor the hybridomas typically will include hypoxanthine, aminopterin, andthymidine (HAT medium), which substances prevent the growth ofHGPRT-deficient cells.

Preferred myeloma cells are those that fuse efficiently, support stablehigh-level production of antibody by the selected antibody-producingcells, and are sensitive to a medium such as HAT medium. Among these,preferred myeloma cell lines are murine myeloma lines, such as thosederived from MOPC-21 and MPC-11 mouse tumors available from the SalkInstitute Cell Distribution Center, San Diego, Calif. USA, and SP-2cells available from the American Type Culture Collection, Rockville,Md. USA.

Human myeloma and mouse-human heteromyeloma cell lines also have beendescribed for the production of human monoclonal antibodies (Kozbor,1984, J. Immunol., 133:3001; Brodeur et al., Monoclonal AntibodyProduction Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc.,New York, 1987)). Culture medium in which hybridoma cells are growing isassayed for production of monoclonal antibodies directed against theantigen. Preferably, the binding specificity of monoclonal antibodiesproduced by hybridoma cells is determined by immunoprecipitation or byan in vitro binding assay, such as radioimmunoassay (RIA) orenzyme-linked immuno-absorbent assay (ELISA). The binding affinity ofthe monoclonal antibody can, for example, be determined by the Scatchardanalysis of Munson et al., 1980, Anal. Biochem., 107:220.

After hybridoma cells are identified that produce antibodies of thedesired specificity, affinity, and/or activity, the clones may besubcloned by limiting dilution procedures and grown by standard methods(Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103,Academic Press, 1986). Suitable culture media for this purpose include,for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cellsmay be grown in vivo as ascites tumors in an animal. The monoclonalantibodies secreted by the subclones are suitably separated from theculture medium, ascites fluid, or serum by conventional immunoglobulinpurification procedures such as, for example, protein A-Sepharose,hydroxylapatite chromatography, gel electrophoresis, dialysis, oraffinity chromatography.

Alternative to preparing monoclonal antibody-secreting hybridomas, amonoclonal antibody directed against a CML progression protein or afragment thereof can be identified and isolated by screening arecombinant combinatorial immunoglobulin library (e.g., an antibodyphage display library) with the CML progression protein or the fragment.Kits for generating and screening phage display libraries arecommercially available (e.g., Pharmacia Recombinant Phage AntibodySystem, Catalog No. 27-9400-01; and the Stratagene antigen SurfZAP™Phage Display Kit, Catalog No. 240612). Additionally, examples ofmethods and reagents particularly amenable for use in generating andscreening antibody display library can be found in, for example, U.S.Pat. Nos. 5,223,409 and 5,514,548; PCT Publication No. WO 92/18619; PCTPublication No. WO 91/17271; PCT Publication No. WO 92/20791; PCTPublication No. WO 92/15679; PCT Publication No. WO 93/01288; PCTPublication No. WO 92/01047; PCT Publication No. WO 92/09690; PCTPublication No. WO 90/02809; Fuchs et al., 1991, Bio/Technology9:1370-1372; Hay et al., 1992, Hum. Antibod. Hybridomas 3:81-85; Huse etal., 1989, Science 246:1275-1281; Griffiths et al., 1993, EMBO J.12:725-734.

In addition, techniques developed for the production of “chimericantibodies” (Morrison, et al., 1984, Proc. Natl. Acad. Sci., 81,6851-6855; Neuberger, et al., 1984, Nature 312, 604-608; Takeda, et al.,1985, Nature, 314, 452-454) by splicing the genes from a mouse antibodymolecule of appropriate antigen specificity together with genes from ahuman antibody molecule of appropriate biological activity can be used.A chimeric antibody is a molecule in which different portions arederived from different animal species, such as those having a variableregion derived from a murine mAb and a human immunoglobulin constantregion. (See, e.g., Cabilly et al., U.S. Pat. No. 4,816,567; and Boss etal., U.S. Pat. No. 4,816,397, which are incorporated herein by referencein their entirety.)

Humanized antibodies are antibody molecules from non-human specieshaving one or more complementarity determining regions (CDRs) from thenon-human species and a framework region from a human immunoglobulinmolecule. (see e.g., U.S. Pat. No. 5,585,089, which is incorporatedherein by reference in its entirety.) Such chimeric and humanizedmonoclonal antibodies can be produced by recombinant DNA techniquesknown in the art, for example using methods described in PCT PublicationNo. WO 87/02671; European Patent Application 184,187; European PatentApplication 171,496; European Patent Application 173,494; PCTPublication No. WO 86/01533; U.S. Pat. Nos. 4,816,567 and 5,225,539;European Patent Application 125,023; Better et al., 1988, Science240:1041-1043; Liu et al., 1987, Proc. Natl. Acad. Sci. USA84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al.,1987, Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al., 1987,Canc. Res. 47:999-1005; Wood et al., 1985, Nature 314:446-449; Shaw etal., 1988, J. Natl. Cancer Inst. 80:1553-1559; Morrison 1985, Science229:1202-1207; Oi et al., 1986, Bio/Techniques 4:214; Jones et al.,1986, Nature 321:552-525; Verhoeyan et al., 1988, Science 239:1534; andBeidler et al., 1988, J. Immunol. 141:4053-4060.

Complementarity determining region (CDR) grafting is another method ofhumanizing antibodies. It involves reshaping murine antibodies in orderto transfer full antigen specificity and binding affinity to a humanframework (Winter et al. U.S. Pat. No. 5,225,539). CDR-graftedantibodies have been successfully constructed against various antigens,for example, antibodies against IL-2 receptor as described in Queen etal., 1989 (Proc. Natl. Acad. Sci. USA 86:10029); antibodies against cellsurface receptors-CAMPATH as described in Riechmann et al. (1988,Nature, 332:323; antibodies against hepatitis B in Cole et al. (1991,Proc. Natl. Acad. Sci. USA 88:2869); as well as against viralantigens-respiratory syncitial virus in Tempest et al. (1991,Bio-Technology 9:267). CDR-grafted antibodies are generated in which theCDRs of the murine monoclonal antibody are grafted into a humanantibody. Following grafting, most antibodies benefit from additionalamino acid changes in the framework region to maintain affinity,presumably because framework residues are necessary to maintain CDRconformation, and some framework residues have been demonstrated to bepart of the antigen binding site. However, in order to preserve theframework region so as not to introduce any antigenic site, the sequenceis compared with established germline sequences followed by computermodeling.

Completely human antibodies are particularly desirable for therapeutictreatment of human patients. Such antibodies can be produced usingtransgenic mice which are incapable of expressing endogenousimmunoglobulin heavy and light chain genes, but which can express humanheavy and light chain genes. The transgenic mice are immunized in thenormal fashion with a CML progression protein.

Monoclonal antibodies directed against a CML progression protein can beobtained using conventional hybridoma technology. The humanimmunoglobulin transgenes harbored by the transgenic mice rearrangeduring B cell differentiation, and subsequently undergo class switchingand somatic mutation. Thus, using such a technique, it is possible toproduce therapeutically useful IgG, IgA and IgE antibodies. For anoverview of this technology for producing human antibodies, see Lonbergand Huszar (1995, Int. Rev. Immunol. 13:65-93). For a detaileddiscussion of this technology for producing human antibodies and humanmonoclonal antibodies and protocols for producing such antibodies, seee.g., U.S. Pat. No. 5,625,126; U.S. Pat. No. 5,633,425; U.S. Pat. No.5,569,825; U.S. Pat. No. 5,661,016; and U.S. Pat. No. 5,545,806. Inaddition, companies such as Abgenix, Inc. (Freemont, Calif., see, forexample, U.S. Pat. No. 5,985,615) and Medarex, Inc. (Princeton, N.J.),can be engaged to provide human antibodies directed against a CMLprogression protein or a fragment thereof using technology similar tothat described above.

Completely human antibodies which recognize and bind a selected epitopecan be generated using a technique referred to as “guided selection.” Inthis approach a selected non-human monoclonal antibody, e.g., a mouseantibody, is used to guide the selection of a completely human antibodyrecognizing the same epitope (Jespers et al., 1994, Bio/technology12:899-903).

A pre-existing anti-CML progression protein antibody can be used toisolate additional antigens of the CML progression protein by standardtechniques, such as affinity chromatography or immunoprecipitation foruse as immunogens. Moreover, such an antibody can be used to detect theprotein (e.g., in a cellular lysate or cell supernatant) in order toevaluate the abundance and pattern of expression of CML progressionprotein. Detection can be facilitated by coupling the antibody to adetectable substance. Examples of detectable substances include variousenzymes, prosthetic groups, fluorescent materials, luminescentmaterials, bioluminescent materials, and radioactive materials. Examplesof suitable enzymes include horseradish peroxidase, alkalinephosphatase, beta-galactosidase, or acetylcholinesterase; examples ofsuitable prosthetic group complexes include streptavidin/biotin andavidin/biotin; examples of suitable fluorescent materials includeumbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; anexample of a luminescent material includes luminol; examples ofbioluminescent materials include luciferase, luciferin, and aequorin,and examples of suitable radioactive material include 125I, 131I, 35S or3H.

5.8.2. Production of Polyclonal Anti-CML Progression/Target or IMResistance Protein Antibodies

The anti-CML progression protein antibodies can be produced byimmunization of a suitable animal, such as but are not limited to mouse,rabbit, and horse.

An immunogenic preparation comprising a CML progression protein or afragment thereof can be used to prepare antibodies by immunizing asuitable subject (e.g., rabbit, goat, mouse or other mammal). Anappropriate immunogenic preparation can contain, for example,recombinantly expressed or chemically synthesized CML progressionprotein peptide or polypeptide. The preparation can further include anadjuvant, such as Freund's complete or incomplete adjuvant, or similarimmunostimulatory agent.

A fragment of a CML progression protein suitable for use as an immunogencomprises at least a portion of the CML progression protein that is 8amino acids, more preferably 10 amino acids and more preferably still,15 amino acids long.

The invention also provides chimeric or fusion CML progression proteinpolypeptides for use as immunogens. As used herein, a “chimeric” or“fusion” CML progression protein polypeptide comprises all or part of aCML progression protein polypeptide operably linked to a heterologouspolypeptide. Within the fusion CML progression protein polypeptide, theterm “operably linked” is intended to indicate that the CML progressionprotein polypeptide and the heterologous polypeptide are fused in-frameto each other. The heterologous polypeptide can be fused to theN-terminus or C-terminus of the CML progression protein polypeptide.

One useful fusion CML progression protein polypeptide is a GST fusionCML progression protein polypeptide in which the CML progression proteinpolypeptide is fused to the C-terminus of GST sequences. Such fusion CMLprogression protein polypeptides can facilitate the purification of arecombinant CML progression protein polypeptide.

In another embodiment, the fusion CML progression protein polypeptidecontains a heterologous signal sequence at its N-terminus so that theCML progression protein polypeptide can be secreted and purified to highhomogeneity in order to produce high affinity antibodies. For example,the native signal sequence of an immunogen can be removed and replacedwith a signal sequence from another protein. For example, the gp67secretory sequence of the baculovirus envelope protein can be used as aheterologous signal sequence (Current Protocols in Molecular Biology,Ausubel et al., eds., John Wiley & Sons, 1992). Other examples ofeukaryotic heterologous signal sequences include the secretory sequencesof melittin and human placental alkaline phosphatase (Stratagene; LaJolla, Calif.). In yet another example, useful prokaryotic heterologoussignal sequences include the phoA secretory signal and the protein Asecretory signal (Pharmacia Biotech; Piscataway, N.J.).

In yet another embodiment, the fusion CML progression proteinpolypeptide is an immunoglobulin fusion protein in which all or part ofa CML progression protein polypetide is fused to sequences derived froma member of the immunoglobulin protein family. The immunoglobulin fusionproteins can be used as immunogens to produce antibodies directedagainst the CML progression protein polypetide in a subject.

Chimeric and fusion CML progression protein polypeptide can be producedby standard recombinant DNA techniques. In one embodiment, the fusiongene can be synthesized by conventional techniques including automatedDNA synthesizers. Alternatively, PCR amplification of gene fragments canbe carried out using anchor primers which give rise to complementaryoverhangs between two consecutive gene fragments which can subsequentlybe annealed and reamplified to generate a chimeric gene sequence (e.g.,Ausubel et al., supra). Moreover, many expression vectors arecommercially available that already encode a fusion domain (e.g., a GSTpolypeptide). A nucleic acid encoding an immunogen can be cloned intosuch an expression vector such that the fusion domain is linked in-frameto the polypeptide.

The CML progression protein immunogenic preparation is then used toimmunize a suitable animal. Preferably, the animal is a specializedtransgenic animal that can secret human antibody. Non-limiting examplesinclude transgenic mouse strains which can be used to produce apolyclonal population of antibodies directed to a specific pathogen(Fishwild et al., 1996, Nature Biotechnology 14:845-851; Mendez et al.,1997, Nature Genetics 15:146-156). In one embodiment of the invention,transgenic mice that harbor the unrearranged human immunoglobulin genesare immunized with the target immunogens. After a vigorous immuneresponse against the immunogenic preparation has been elicited in themice, the blood of the mice are collected and a purified preparation ofhuman IgG molecules can be produced from the plasma or serum. Any methodknown in the art can be used to obtain the purified preparation of humanIgG molecules, including but is not limited to affinity columnchromatography using anti-human IgG antibodies bound to a suitablecolumn matrix. Anti-human IgG antibodies can be obtained from anysources known in the art, e.g., from commercial sources such as DakoCorporation and ICN. The preparation of IgG molecules produced comprisesa polyclonal population of IgG molecules that bind to the immunogen orimmunogens at different degree of affinity. Preferably, a substantialfraction of the preparation contains IgG molecules specific to theimmunogen or immunogens. Although polyclonal preparations of IgGmolecules are described, it is understood that polyclonal preparationscomprising any one type or any combination of different types ofimmunoglobulin molecules are also envisioned and are intended to bewithin the scope of the present invention.

A population of antibodies directed to a CML progression protein can beproduced from a phage display library. Polyclonal antibodies can beobtained by affinity screening of a phage display library having asufficiently large and diverse population of specificities with a CMLprogression protein or a fragment thereof. Examples of methods andreagents particularly amenable for use in generating and screeningantibody display library can be found in, for example, U.S. Pat. Nos.5,223,409 and 5,514,548; PCT Publication No. WO 92/18619; PCTPublication No. WO 91/17271; PCT Publication No. WO 92/20791; PCTPublication No. WO 92/15679; PCT Publication No. WO 93/01288; PCTPublication No. WO 92/01047; PCT Publication No. WO 92/09690; PCTPublication No. WO 90/02809; Fuchs et al., 1991, Bio/Technology9:1370-1372; Hay et al., 1992, Hum. Antibod. Hybridomas 3:81-85; Huse etal., 1989, Science 246:1275-1281; Griffiths et al., 1993, EMBO J.12:725-734. A phage display library permits selection of desiredantibody or antibodies from a very large population of specificities. Anadditional advantage of a phage display library is that the nucleicacids encoding the selected antibodies can be obtained conveniently,thereby facilitating subsequent construction of expression vectors.

In other preferred embodiments, the population of antibodies directed toa CML progression protein or a fragment thereof is produced by a methodusing the whole collection of selected displayed antibodies withoutclonal isolation of individual members as described in U.S. Pat. No.6,057,098, which is incorporated by reference herein in its entirety.Polyclonal antibodies are obtained by affinity screening of a phagedisplay library having a sufficiently large repertoire of specificitieswith, e.g., an antigenic molecule having multiple epitopes, preferablyafter enrichment of displayed library members that display multipleantibodies. The nucleic acids encoding the selected display antibodiesare excised and amplified using suitable PCR primers. The nucleic acidscan be purified by gel electrophoresis such that the full length nucleicacids are isolated. Each of the nucleic acids is then inserted into asuitable expression vector such that a population of expression vectorshaving different inserts is obtained. The population of expressionvectors is then expressed in a suitable host.

5.8.3 Production of Antibody-Drug Conjugates Targeting a CMLProgression/Target or IM Resistance Protein

Cancer cells can be targeted and killed using anti-CML progressionprotein antibody-drug conjugates that target an advanced phase CMLhematopoetic stem cell and/or immature myeloid cell expressing a CMLprogression protein on its surface, e.g., PRAME. For example, anantibody specific for a CML progression protein may be conjugated to atherapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidalagent, or a radioactive metal ion. Antibody-drug conjugates can beprepared by method known in the art (see, e.g., Immunoconjugates, Vogel,ed. 1987; Targeted Drugs, Goldberg, ed. 1983; Antibody Mediated DeliverySystems, Rodwell, ed. 1988). Therapeutic drugs, such as but are notlimited to, paclitaxol, cytochalasin B, gramicidin D, ethidium bromide,emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine,colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione,mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone,glucocorticoids, procaine, tetracaine, lidocaine, propranolol, andpuromycin and analogs or homologs thereof, can be conjugated to anti-CMLprogression protein antibodies. Other therapeutic agents that can beconjugated to anti-CML progression protein antibodies include, but arenot limited to, antimetabolites, e.g., methotrexate, 6-mercaptopurine,6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylatingagents, e.g., mechlorethamine, thioepa chlorambucil, melphalan,carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan,dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamineplatinum (II) (DDP) cisplatin; anthracyclines, e.g., daunorubicin(daunomycin) and doxorubicin; antibiotics, e.g., dactinomycin(actinomycin), bleomycin, mithramycin, anthramycin (AMC); andanti-mitotic agents, e.g., vincristine and vinblastine. The therapeuticagents that can be conjugated to anti-CML progression protein antibodiesmay also be a protein or polypeptide possessing a desired biologicalactivity. Other chemotherapeutic agents known in the art, such as thosedescribed in Section 5.8.5, infra, can also be conjugated with such ananti-CML progression protein antibody. Such proteins may include, forexample, a toxin such as abrin, ricin A, pseudomonas exotoxin, ordiphtheria toxin.

The drug molecules can be linked to the anti-CML progression proteinantibody via a linker. Any suitable linker can be used for thepreparation of such conjugates. In some embodiments, the linker can be alinker that allows the drug molecules to be released from the conjugatesin unmodified form at the target site.

The antibodies can also be used diagnostically to, for example, monitorthe presence of cancer cells as part of a clinical testing procedure to,e.g., determine the efficacy of a given treatment regimen. Detection canbe facilitated by coupling the antibody to a detectable substance.Examples of detectable substances include various enzymes, prostheticgroups, fluorescent materials, luminescent materials, bioluminescentmaterials, radioactive materials, positron emitting metals using variouspositron emission tomographies, and nonradioactive paramagnetic metalions. See generally U.S. Pat. No. 4,741,900 for metal ions which can beconjugated to antibodies for use as diagnostics according to the presentinvention. Examples of suitable enzymes include horseradish peroxidase,alkaline phosphatase, beta-galactosidase, or acetylcholinesterase;examples of suitable prosthetic group complexes includestreptavidin/biotin and avidin/biotin; examples of suitable fluorescentmaterials include fluorescent proteins, e.g., green fluorescent protein(GFP), umbelliferone, fluorescein, fluorescein isothiocyanate,rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride orphycoerythrin; an example of a luminescent material includes luminol;examples of bioluminescent materials include luciferase, luciferin, andaequorin, and examples of suitable radioactive material include ¹²⁵I,¹³¹I, ¹¹¹In, ¹⁷⁷Lu, ⁹⁰Y or ⁹⁹Tc.

Techniques for conjugating therapeutic moieties to antibodies are wellknown, see, e.g., Arnon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “ThePreparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”,Immunol. Rev., 62:119-58 (1982); each of which is incorporated herein byreference.

Alternatively, an antibody can be conjugated to a second antibody toform an antibody heteroconjugate as described by Segal in U.S. Pat. No.4,676,980, which is incorporated herein by reference.

5.8.4 Production of Peptides

A CML progression protein-binding peptide or polypeptide or peptide orpolypeptide of a CML progression protein may be produced by recombinantDNA technology using techniques well known in the art. Thus, thepolypeptide or peptide can be produced by expressing nucleic acidcontaining sequences encoding the polypeptide or peptide. Methods whichare well known to those skilled in the art can be used to constructexpression vectors containing coding sequences and appropriatetranscriptional and translational control signals. These methodsinclude, for example, in vitro recombinant DNA techniques, synthetictechniques, and in vivo genetic recombination. See, for example, thetechniques described in Sambrook et al., 1989, supra, and Ausubel etal., 1989, supra. Alternatively, RNA capable of encoding CML progressionprotein polypeptide sequences may be chemically synthesized using, forexample, synthesizers. See, for example, the techniques described in“Oligonucleotide Synthesis”, 1984, Gait, M. J. ed., IRL Press, Oxford,which is incorporated herein by reference in its entirety.

5.8.5 Chemotherapeutic Drugs

The invention can be practiced with any known chemotherapeutic drugs,including but not limited to DNA damaging agents, anti-metabolites,anti-mitotic agents, or a combination of two or more of such knownanti-cancer agents.

DNA damage agents cause chemical damage to DNA and/or RNA. DNA damageagents can disrupt DNA replication or cause the generation of nonsenseDNA or RNA. DNA damaging agents include but are not limited totopoisomerase inhibitor, DNA binding agent, and ionizing radiation. Atopoisomerase inhibitor that can be used in conjunction with theinvention can be a topoisomerase I (Topo I) inhibitor, a topoisomeraseII (Topo II) inhibitor, or a dual topoisomerase I and II inhibitor. Atopo I inhibitor can be for example from any of the following classes ofcompounds: camptothecin analogue (e.g., karenitecin, aminocamptothecin,lurtotecan, topotecan, irinotecan, BAY 56-3722, rubitecan, GI14721,exatecan mesylate), rebeccamycin analogue, PNU 166148, rebeccamycin,TAS-103, camptothecin (e.g., camptothecin polyglutamate, camptothecinsodium), intoplicine, ecteinascidin 743, J-107088, pibenzimol Examplesof preferred topo I inhibitors include but are not limited tocamptothecin, topotecan (hycaptamine), irinotecan (irinotecanhydrochloride), belotecan, or an analogue or derivative of any of theforegoing.

A topo II inhibitor that can be used in conjunction with the inventioncan be for example from any of the following classes of compounds:anthracycline antibiotics (e.g., carubicin, pirarubicin, daunorubicincitrate liposomal, daunomycin, 4-iodo-4-doxydoxorubicin, doxorubicin,n,n-dibenzyl daunomycin, morpholinodoxorubicin, aclacinomycinantibiotics, duborimycin, menogaril, nogalamycin, zorubicin, epirubicin,marcellomycin, detorubicin, annamycin, 7-cyanoquinocarcinol,deoxydoxorubicin, idarubicin, GPX-100, MEN-10755, valrubicin, KRN5500),epipodophyllotoxin compound (e.g., podophyllin, teniposide, etoposide,GL331, 2-ethylhydrazide), anthraquinone compound (e.g., ametantrone,bisantrene, mitoxantrone, anthraquinone), ciprofloxacin, acridinecarboxamide, amonafide, anthrapyrazole antibiotics (e.g., teloxantrone,sedoxantrone trihydrochloride, piroxantrone, anthrapyrazole,losoxantrone), TAS-103, fostriecin, razoxane, XK469R, XK469,chloroquinoxaline sulfonamide, merbarone, intoplicine, elsamitrucin,CI-921, pyrazoloacridine, elliptinium, amsacrine. Examples of preferredtopo II inhibitors include but are not limited to doxorubicin(Adriamycin), etoposide phosphate (etopofos), teniposide, sobuzoxane, oran analogue or derivative of any of the foregoing.

DNA binding agents that can be used in conjunction with the inventioninclude but are not limited to a DNA groove binding agent, e.g., DNAminor groove binding agent; DNA crosslinking agent; intercalating agent;and DNA adduct forming agent. A DNA minor groove binding agent can be ananthracycline antibiotic, mitomycin antibiotic (e.g., porfiromycin,KW-2149, mitomycin B, mitomycin A, mitomycin C), chromomycin A3,carzelesin, actinomycin antibiotic (e.g., cactinomycin, dactinomycin,actinomycin F1), brostallicin, echinomycin, bizelesin, duocarmycinantibiotic (e.g., KW 2189), adozelesin, olivomycin antibiotic,plicamycin, zinostatin, distamycin, MS-247, ecteinascidin 743,amsacrine, anthramycin, and pibenzimol, or an analogue or derivative ofany of the foregoing.

DNA crosslinking agents include but are not limited to antineoplasticalkylating agent, methoxsalen, mitomycin antibiotic, psoralen. Anantineoplastic alkylating agent can be a nitrosourea compound (e.g.,cystemustine, tauromustine, semustine, PCNU, streptozocin, SarCNU,CGP-6809, carmustine, fotemustine, methylnitrosourea, nimustine,ranimustine, ethylnitrosourea, lomustine, chlorozotocin), mustard agent(e.g., nitrogen mustard compound, such as spiromustine, trofosfamide,chlorambucil, estramustine, 2,2,2-trichlorotriethylamine, prednimustine,novembichin, phenamet, glufosfamide, peptichemio, ifosfamide,defosfamide, nitrogen mustard, phenesterin, mannomustine,cyclophosphamide, melphalan, perfosfamide, mechlorethamine oxidehydrochloride, uracil mustard, bestrabucil, DHEA mustard, tallimustine,mafosfamide, aniline mustard, chlornaphazine; sulfur mustard compound,such as bischloroethylsulfide; mustard prodrug, such as TLK286 andZD2767), ethylenimine compound (e.g., mitomycin antibiotic,ethylenimine, uredepa, thiotepa, diaziquone, hexamethylene bisacetamide,pentamethylmelamine, altretamine, carzinophilin, triaziquone,meturedepa, benzodepa, carboquone), alkylsulfonate compound (e.g.,dimethylbusulfan, Yoshi-864, improsulfan, piposulfan, treosulfan,busulfan, hepsulfam), epoxide compound (e.g., anaxirone, mitolactol,dianhydrogalactitol, teroxirone), miscellaneous alkylating agent (e.g.,ipomeanol, carzelesin, methylene dimethane sulfonate, mitobronitol,bizelesin, adozelesin, piperazinedione, VNP40101M, asaley,6-hydroxymethylacylfulvene, EO9, etoglucid, ecteinascidin 743,pipobroman), platinum compound (e.g., ZD0473, liposomal-cisplatinanalogue, satraplatin, BBR 3464, spiroplatin, ormaplatin, cisplatin,oxaliplatin, carboplatin, lobaplatin, zeniplatin, iproplatin), triazenecompound (e.g., imidazole mustard, CB10-277, mitozolomide, temozolomide,procarbazine, dacarbazine), picoline compound (e.g., penclomedine), oran analogue or derivative of any of the foregoing. Examples of preferredalkylating agents include but are not limited to cisplatin,dibromodulcitol, fotemustine, ifosfamide (ifosfamid), ranimustine(ranomustine), nedaplatin (latoplatin), bendamustine (bendamustinehydrochloride), eptaplatin, temozolomide (methazolastone), carboplatin,altretamine (hexamethylmelamine), prednimustine, oxaliplatin(oxalaplatinum), carmustine, thiotepa, leusulfon (busulfan), lobaplatin,cyclophosphamide, bisulfan, melphalan, and chlorambucil, or an analogueor derivative of any of the foregoing.

Intercalating agents can be an anthraquinone compound, bleomycinantibiotic, rebeccamycin analogue, acridine, acridine carboxamide,amonafide, rebeccamycin, anthrapyrazole antibiotic, echinomycin,psoralen, LU 79553, BW A773U, crisnatol mesylate,benzo(a)pyrene-7,8-diol-9,10-epoxide, acodazole, elliptinium,pixantrone, or an analogue or derivative of any of the foregoing.

DNA adduct forming agents include but are not limited to enediyneantitumor antibiotic (e.g., dynemicin A, esperamicin A1, zinostatin,dynemicin, calicheamicin gamma 11), platinum compound, carmustine,tamoxifen (e.g., 4-hydroxy-tamoxifen), psoralen, pyrazinediazohydroxide, benzo(a)pyrene-7,8-diol-9,10-epoxide, or an analogue orderivative of any of the foregoing.

Anti-metabolites block the synthesis of nucleotides ordeoxyribonucleotides, which are necessary for making DN, therebypreventing cells from replicating. Anti-metabolites include but are notlimited to cytosine, arabinoside, floxuridine, 5-fluorouracil (5-FU),mercaptopurine, gemcitabine, hydroxyurea (HU), and methotrexate (MTX).

Anti-mitotic agents disrupt the development of the mitotic spindlethereby interfering with tumor cell proliferation. Anti-mitotic agentsinclude but are not limited to Vinblastine, Vincristine, and Pacitaxel(Taxol). Anti-mitotic agents also includes agents that target theenzymes that regulate mitosis, e.g., agents that target kinesin spindleprotein (KSP), e.g., L-001000962-000Y.

5.9. KITS

The invention provides kits that are useful in determining the stage ofCML in a patient. The kits of the present invention comprise one or moreprobes and/or primers for each of at least 5, 10, 20, 30, 40, 50, 60,70, 80, or 100 gene products that are encoded by the respectively markergenes listed in Tables 1a and/or 1b or functional equivalents of suchgenes, wherein the probes and/or primers are at least 50%, 75%, 80%,85%, 90%, 95%, 97%, 98%, 99% or 100% of the total probes and/or primersin the kit. The probes of marker genes may be part of an array, or thebiomarker(s) may be packaged separately and/or individually.

The invention provides kits that are useful in determining theprogression of CML in a patient. The kits of the present inventioncomprise one or more probes and/or primers for each of at least 5, 10,20, 30, 40, 50, 60, 70, 80, or 100 gene products that are encoded by therespectively marker genes listed in Tables 2a and/or 2b or functionalequivalents of such genes, wherein the probes and/or primers are atleast 50%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the totalprobes and/or primers in the kit. In a preferred embodiment, the kitscomprise one or more probes and/or primers for each of at least 5, 10,20, 30, 40, 50, 60, 70, 80, or 100 gene products that are encoded by therespectively marker genes listed in Table 4 or functional equivalents ofsuch genes, wherein the probes and/or primers are at least 50%, 75%,80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the total probes and/orprimers in the kit. The probes of marker genes may be part of an array,or the biomarker(s) may be packaged separately and/or individually.

In one embodiment, the invention provides kits comprising probes thatare immobilized at an addressable position on a substrate, e.g., in amicroarray. In a particular embodiment, the invention provides such amicroarray.

The kits of the present invention may also contain probes that can beused to detect protein products of the marker genes of the invention. Ina specific embodiment, the invention provides a kit comprises aplurality of antibodies that specifically bind a plurality of at least5, 10, 20, 30, 40, 50, 60, 70, 80, or 100 proteins that are encoded bythe respectively marker genes listed in Tables 1a and/or 1b or any oneof Tables 2a and/or 2b and 5a and/or 5b or functional equivalents ofsuch genes, wherein the antibodies are at least 50%, 75%, 80%, 85%, 90%,95%, 97%, 98%, 99% or 100% of the total antibodies in the kit. Inaccordance with this embodiment, the kit may comprise a set ofantibodies or functional fragments or derivatives thereof (e.g., Fab,F(ab′)₂, Fv, or scFv fragments). In accordance with this embodiment, thekit may include antibodies, fragments or derivatives thereof (e.g., Fab,F(ab′)₂, Fv, or scFv fragments) that are specific for these proteins. Inone embodiment, the antibodies may be detectably labeled.

The kits of the present invention may also include reagents such asbuffers, or other reagents that can be used in obtaining the markerprofile. Prevention of the action of microorganisms can be ensured bythe inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents such as sugars, sodiumchloride, and the like.

In some embodiments of the invention, the kits of the present inventioncomprise a microarray. The microarray can be any of the microarraysdescribed above, e.g., in Section 5.6.1, optionally in a sealedcontainer. In one embodiment this microarray comprises a plurality ofprobe spots, wherein at least 20%, 40%, 60%, 80%, or 90% of the probespots in the plurality of probe spots correspond to marker genes listedin Tables 1a and/or 1b or any one of Tables 2a and/or 2b and 4.

In still other embodiments, the kits of the invention may furthercomprise a computer program product for use in conjunction with acomputer system, wherein the computer program product comprises acomputer readable storage medium and a computer program mechanismembedded therein. In such kits, the computer program mechanism comprisesinstructions for prediction of prognosis using a marker profile obtainedwith the reagents of the kits.

In still other embodiments, the kits of the present invention comprise acomputer having a central processing unit and a memory coupled to thecentral processing unit. The memory stores instructions for predictionof prognosis using a marker profile obtained with the reagents of thekits.

5.10. Pharmaceutical Formulations and Routes of Administration

The compounds that can be used to modulate the expression of the CMLprogression genes or the activity of their gene products can beadministered to a patient at therapeutically effective doses. Atherapeutically effective dose refers to that amount of the compoundsufficient to result in normal expression or activity level.

5.10.1. Effective Dose

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compounds which exhibit large therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage touninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

5.10.2. Formulations and Use

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morepharmaceutically acceptable carriers or excipients.

Thus, the compounds and their pharmaceutically acceptable salts andsolvates may be formulated for administration by inhalation orinsufflation (either through the mouth or the nose) or oral, buccal,parenteral or rectal administration.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium hydrogen phosphate); lubricants (e.g., magnesiumstearate, talc or silica); disintegrants (e.g., potato starch or sodiumstarch glycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetableoils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates orsorbic acid). The preparations may also contain buffer salts, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration.

5.10.3. Routes of Administration

Suitable routes of administration may, for example, include oral,rectal, transmucosal, transdermal, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections.

Alternately, one may administer the compound in a local rather thansystemic manner, for example, via injection of the compound directlyinto an affected area, often in a depot or sustained releaseformulation.

Furthermore, one may administer the drug in a targeted drug deliverysystem, for example, in a liposome coated with an antibody specific foraffected cells. The liposomes will be targeted to and taken upselectively by the cells.

5.10.4. Packaging

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. Compositions comprisinga compound formulated in a compatible pharmaceutical carrier may also beprepared, placed in an appropriate container, and labeled for treatmentof an indicated condition. Suitable conditions indicated on the labelmay include treatment of a disease such as one characterized by aberrantor excessive expression or activity of a CML progression protein.

5.10.5. Combination Therapy

In a combination therapy, one or more compositions of the presentinvention can be administered before, at the same time as, or after theadministration of a chemotherapeutic agent. In one embodiment, thecompositions of the invention are administered before the administrationof an chemotherapeutic agent (i.e., the agent that modulates expressionor activity of a CML progression gene or imatinib mesylate resistancegene and/or encoded protein is for sequential or concurrent use with oneor more chemotherapeutic agents). In one embodiment, the composition ofthe invention and a chemotherapeutic agent are administered in asequence and within a time interval such that the composition of theinvention and a chemotherapeutic agent can act together to provide anincreased benefit than if they were administered alone. In anotherembodiment, the composition of the invention and a chemotherapeuticagent are administered sufficiently close in time so as to provide thedesired therapeutic outcome. The time intervals between theadministration of the compositions of the invention and achemotherapeutic agent can be determined by routine experiments that arefamiliar to one skilled person in the art. In one embodiment, achemotherapeutic agent is given to the patient after the level of theCML progression gene or imatinib mesylate resistance gene and/or encodedprotein reaches a desirable threshold. The level of a CML progressiongene or imatinib mesylate resistance gene and/or encoded protein can bedetermined by using any techniques known in the art such as thosedescribed in Section 5.3., infra.

The composition of the invention and a chemotherapeutic agent can beadministered simultaneously or separately, in any appropriate form andby any suitable route. In one embodiment, the composition of theinvention and the chemotherapeutic agent are administered by differentroutes of administration. In an alternate embodiment, each isadministered by the same route of administration. The composition of theinvention and the chemotherapeutic agent can be administered at the sameor different sites, e.g. arm and leg.

In various embodiments, such as those described above, the compositionof the invention and a chemotherapeutic agent are administered less than1 hour apart, at about 1 hour apart, 1 hour to 2 hours apart, 2 hours to3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hoursapart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apartor no more than 48 hours apart, or no more than 1 week or 2 weeks or 1month or 3 months apart. As used herein, the word about means within10%. In other embodiments, the composition of the invention and achemotherapeutic agent are administered 2 to 4 days apart, 4 to 6 daysapart, 1 week apart, 1 to 2 weeks apart, 2 to 4 weeks apart, one monthapart, 1 to 2 months apart, or 2 or more months apart. In preferredembodiments, the composition of the invention and a chemotherapeuticagent are administered in a time frame where both are still active. Oneskilled in the art would be able to determine such a time frame bydetermining the half life of each administered component. In separate orin the foregoing embodiments, the composition of the invention and achemotherapeutic agent are administered less than 2 weeks, one month,six months, 1 year or 5 years apart.

In another embodiment, the compositions of the invention areadministered at the same time or at the same patient visit, as thechemotherapeutic agent.

In still another embodiment, one or more of the compositions of theinvention are administered both before and after the administration of achemotherapeutic agent. Such administration can be beneficial especiallywhen the chemotherapeutic agent has a longer half life than that of theone or more of the compositions of the invention used in the treatment.

In one embodiment, the chemotherapeutic agent is administered daily andthe composition of the invention is administered once a week for thefirst 4 weeks, and then once every other week thereafter. In oneembodiment, the chemotherapeutic agent is administered daily and thecomposition of the invention is administered once a week for the first 8weeks, and then once every other week thereafter.

In certain embodiments, the composition of the invention and thechemotherapeutic agent are cyclically administered to a subject. Cyclingtherapy involves the administration of the composition of the inventionfor a period of time, followed by the administration of achemotherapeutic agent for a period of time and repeating thissequential administration. Cycling therapy can reduce the development ofresistance to one or more of the therapies, avoid or reduce the sideeffects of one of the therapies, and/or improve the efficacy of thetreatment. In such embodiments, the invention contemplates thealternating administration of the composition of the invention followedby the administration of a chemotherapeutic agent 4 to 6 days later,preferable 2 to 4 days, later, more preferably 1 to 2 days later,wherein such a cycle may be repeated as many times as desired.

In certain embodiments, the composition of the invention and achemotherapeutic agent are alternately administered in a cycle of lessthan 3 weeks, once every two weeks, once every 10 days or once everyweek. In a specific embodiment of the invention, one cycle can comprisethe administration of a chemotherapeutic agent by infusion over 90minutes every cycle, 1 hour every cycle, or 45 minutes every cycle. Eachcycle can comprise at least 1 week of rest, at least 2 weeks of rest, atleast 3 weeks of rest. In an embodiment, the number of cyclesadministered is from 1 to 12 cycles, more typically from 2 to 10 cycles,and more typically from 2 to 8 cycles.

It will be apparent to one skilled person in the art that anycombination of different timing of the administration of thecompositions of the invention and a chemotherapeutic agent can be used.For example, when the chemotherapeutic agent has a longer half life thanthat of the composition of the invention, it is preferable to administerthe compositions of the invention before and after the administration ofthe chemotherapeutic agent.

The frequency or intervals of administration of the compositions of theinvention depends on the desired level of the CML progression gene orimatinib mesylate resistance gene and/or encoded protein, which can bedetermined by any of the techniques known in the art, e.g., thosetechniques described infra. The administration frequency of thecompositions of the invention can be increased or decreased when thelevel of the CML progression gene or imatinib mesylate resistance geneand/or encoded protein changes either higher or lower from the desiredlevel.

5.11. Implementation Systems and Methods

The analytical methods of the present invention can preferably beimplemented using a computer system, such as the computer systemdescribed in this section, according to the following programs andmethods. Such a computer system can also preferably store and manipulatemeasured signals obtained in various experiments that can be used by acomputer system implemented with the analytical methods of thisinvention. Accordingly, such computer systems are also considered partof the present invention.

An exemplary computer system suitable from implementing the analyticmethods of this invention is illustrated in FIG. 8. Computer system 801is illustrated here as comprising internal components and as beinglinked to external components. The internal components of this computersystem include one or more processor elements 802 interconnected with amain memory 803. For example, computer system 801 can be an IntelPentium IV®-based processor of 2 GHZ or greater clock rate and with 256MB or more main memory. In a preferred embodiment, computer system 801is a cluster of a plurality of computers comprising a head “node” andeight sibling “nodes,” with each node having a central processing unit(“CPU”). In addition, the cluster also comprises at least 128 MB ofrandom access memory (“RAM”) on the head node and at least 256 MB of RAMon each of the eight sibling nodes. Therefore, the computer systems ofthe present invention are not limited to those consisting of a singlememory unit or a single processor unit.

The external components can include a mass storage 804. This massstorage can be one or more hard disks that are typically packagedtogether with the processor and memory. Such hard disk are typically of10 GB or greater storage capacity and more preferably have at least 40GB of storage capacity. For example, in a preferred embodiment,described above, wherein a computer system of the invention comprisesseveral nodes, each node can have its own hard drive. The head nodepreferably has a hard drive with at least 10 GB of storage capacitywhereas each sibling node preferably has a hard drive with at least 40GB of storage capacity. A computer system of the invention can furthercomprise other mass storage units including, for example, one or morefloppy drives, one more CD-ROM drives, one or more DVD drives or one ormore DAT drives.

Other external components typically include a user interface device 805,which is most typically a monitor and a keyboard together with agraphical input device 806 such as a “mouse.” The computer system isalso typically linked to a network link 807 which can be, e.g., part ofa local area network (“LAN”) to other, local computer systems and/orpart of a wide area network (“WAN”), such as the Internet, that isconnected to other, remote computer systems. For example, in thepreferred embodiment, discussed above, wherein the computer systemcomprises a plurality of nodes, each node is preferably connected to anetwork, preferably an NFS network, so that the nodes of the computersystem communicate with each other and, optionally, with other computersystems by means of the network and can thereby share data andprocessing tasks with one another.

Loaded into memory during operation of such a computer system areseveral software components that are also shown schematically in FIG. 8.The software components comprise both software components that arestandard in the art and components that are special to the presentinvention. These software components are typically stored on massstorage such as the hard drive 804, but can be stored on other computerreadable media as well including, for example, one or more floppy disks,one or more CD-ROMs, one or more DVDs or one or more DATs. Softwarecomponent 810 represents an operating system which is responsible formanaging the computer system and its network interconnections. Theoperating system can be, for example, of the Microsoft Windows™ familysuch as Windows 95, Window 98, Windows NT, Windows 2000 or Windows XP.Alternatively, the operating software can be a Macintosh operatingsystem, a UNIX operating system or a LINUX operating system. Softwarecomponents 811 comprises common languages and functions that arepreferably present in the system to assist programs implementing methodsspecific to the present invention. Languages that can be used to programthe analytic methods of the invention include, for example, C and C++,FORTRAN, PERL, HTML, JAVA, and any of the UNIX or LINUX shell commandlanguages such as C shell script language. The methods of the inventioncan also be programmed or modeled in mathematical software packages thatallow symbolic entry of equations and high-level specification ofprocessing, including specific algorithms to be used, thereby freeing auser of the need to procedurally program individual equations andalgorithms. Such packages include, e.g., Matlab from Mathworks (Natick,Mass.), Mathematica from Wolfram Research (Champaign, Ill.) or S-Plusfrom MathSoft (Seattle, Wash.).

Software component 812 comprises any analytic methods of the presentinvention described supra, preferably programmed in a procedurallanguage or symbolic package. For example, software component 812preferably includes programs that cause the processor to implement stepsof accepting a plurality of measured signals and storing the measuredsignals in the memory. For example, the computer system can acceptmeasured signals that are manually entered by a user (e.g., by means ofthe user interface). More preferably, however, the programs cause thecomputer system to retrieve measured signals from a database. Such adatabase can be stored on a mass storage (e.g., a hard drive) or othercomputer readable medium and loaded into the memory of the computer, orthe compendium can be accessed by the computer system by means of thenetwork 807.

In addition to the exemplary program structures and computer systemsdescribed herein, other, alternative program structures and computersystems will be readily apparent to the skilled artisan. Suchalternative systems, which do not depart from the above describedcomputer system and programs structures either in spirit or in scope,are therefore intended to be comprehended within the accompanyingclaims.

6. EXAMPLES

The following examples are presented by way of illustration of thepresent invention, and are not intended to limit the present inventionin any way.

6.1. Identification of Phase-Specific Genes in CML

A set of 91 individual cases of CML, including chronic phase (N=42),accelerated phase by blast count criteria (N=9) or by the occurrence ofadditional clonal cytogenetic changes (N=8), blast crisis (N=28), and 4cases of blast crisis in remission after chemotherapy were used toidentify genes involved in progression from chronic phase to advanceddisease (i.e., accelerated and blast phases). A pool of 200 chronicphase bone marrows was used as the reference. An ANOVA analysis revealed˜3,000 genes differentially expressed across the different phases ofdisease using a minimum statistical significance cutoff of p<10⁻¹¹(Tables 1a and 1b). Sequences of polynucleotide probes used to detectthese genes are listed in Table 8. This set of genes identified in theprogression from chronic to blast phase is referred to here as the“phase reporter” gene set. FIG. 1 shows a “heat map” of the expressionof the 3,000 phase reporter genes across the various phases of CML. Thisillustrates the global change of gene expression as the diseaseprogresses from the chronic phase through the advanced phase of thedisease.

The expression patterns were then examined to determine if progressionof CML best fits a three-step model as often described in the literature(chronic phase to accelerated phase to blast crisis), or a two-stepmodel (chronic phase to advanced phase, i.e., accelerated or blastphase). The gene expression patterns of accelerated phase cases werecompared to those of the blast crisis cases (FIG. 5). The correlationbetween the expression profiles of accelerated cases and those of theblast phase was quite strong (r=0.81). Comparing differentiallyregulated genes between accelerated phase with blast phase, there arevery few phase specific genes, i.e. genes only regulated in one phasebut not in another. These observations suggest that the difference ofgene expression changes between accelerated and blast phase is aquantitative one rather than a qualitative one that requires new geneexpression or repression.

The biological functions of the genes associated with CML phases werealso examined by applying a biological annotation program based on theGO and KEGG annotations. The functional groups most highly correlatedwith progression to blast crisis included increased expression ofnuclear genes, mitochondrial genes, RNA binding genes, proteinbiosynthesis genes, and genes involved in chaperone function, allreflecting the increased proliferation and metabolism of progressivedisease.

Progression was also associated with decreases in the expression levelsof genes involved in structural integrity and adhesion, as well asdecreases in the expression levels of genes involved in inflammatory andimmune response. In addition, several proto-oncogenes and tumorsuppressor genes were differentially expressed with progression. Forexample, N- and Hras, FLT3, yes, AF1q, CBFB, WT1, ORALOV1, PTNN11, andBc1-2 demonstrated increased expression in blast crisis as compared tochronic phase. Analysis of the phase reporter genes suggested a relativedecrease in MAPPK signaling in advanced phase as compared to chronicphase. The progression was also seen as associated with increases inalternative signal pathways. Thus, the cytoplasmic GTP protein Rras2 washighly over-expressed in advanced phases, as was ras signalingcomponents RAB56 and RALGD5. Alterations of cytokine signaling weredemonstrated by an increase in expression of TNF factors SF4 and 7, andSOCS2 and 4.

6.2. Identification of Progression- and Response-Specific Genes

Next, how the phase reporter gene set was influenced by the geneexpression signature of leukemia blasts and how they compared to normalimmature CD34+ cells were investigated. First, the gene expressionsignatures of eight samples of normal CD34+ cells were compared with CMLblast samples containing >70% blasts (FIG. 2 a). It was found that thegene expression pattern of CML blast cells was very similar to normalCD34+ cells, suggesting that “progression” from the chronic phase to theadvanced phase is functionally similar to a block or “reversion” towardsa more primitive hematopoetic cell. To uncover genes that are unique toprogression, the normal CD34+ signatures were mathematically subtractedfrom each of the disease samples and the phase reporter signals weresearched for (FIG. 2 c and FIG. 6). A set of 386 genes (p<10⁻⁸) wereidentified (FIG. 2 c and Tables 2a and 2b). These genes are called the“progression genes.” A set of 368 genes with ANOVA p<0.1% wereidentified as differentially expressed between CML blast crisis andnormal immature CD34+ cells were also identified (FIG. 2 b and Tables 5aand 5b). These genes are called the “target genes.” There were 103 genesoverlapping between these two sets (hypergeometric P-value: 1.3×10⁻⁹⁹).This gene set is enriched in genes that are diagnostic markers ofprogression and novel targets of therapy. Table 3 shows the “top ten”genes that are associated with progression, independent of normal CD34+expression, based on log 10 ratio of expression compared to the chronicphase pool. These genes suggest a deregulation of genes oftranscriptional regulation (GLI2, WT1, FOS, FOSB), signal transduction(SOCS2, Rras2, IL8), and apoptosis (GAS2). Moreover, two HSP 70 subunitsare differentially down-regulated, suggesting an alteration of thiscomponent of the chaperone system in blast crisis. Also significantlyassociated with progression was the surface protein PRAME, which has anunknown function, but has been associated with myeloid malignancy (vanBaren et al. 1998, Br J Haematol 102:1376; Watari et al. 2000, FEBS Lett466:367). Gene functions overrepresented in blast crisis werepredominated by changes in ribosome gene expression and increased in thebeta-catenin/WNT signaling pathway. More significant changes in genefunction were down-regulated in progression, including nucleosomeassembly and chromatin structure, sugar catabolism and metabolism,differentiation, and apoptosis.

6.3. Identification of Signaling Pathways Associated with Progression

Multiple changes in several signaling pathways are represented in theprogression gene set. Again, these genes were seen in the progression ofchronic phase to advanced disease, but are differentially expressedcompared to normal CD34+ cells. There was a deregulation of thebetacatenin/WNT pathway. Expression of the cell surface protein cadherinwas decreased, as was proto-cadhedrin, potentially leading to anactivation of the beta-catenin/WNT signaling pathway by allowing morefree beta-catenin to move to the cytoplasm. Moreover, the myogenesistranscription control gene MDFI (I-mfa), which complexes with axin(therefore potentially increasing free beta-catenin), was increased byapproximately 7-fold. In all, 16 genes associated with the beta-cateninpathway were significantly over-expressed (e.g., PRICKLE1, CSNK1E,PLCB1, FZD2, LRP6, SMAD3, etc.). In summary, these findings stronglysuggest aberrant activation of the betacatenin/WNT pathway during CMLprogression. Moreover, progression appears to be associated with aremodeling of several cytoskeletal and adhesion molecules, which mayplay a role in regulating proliferation. Thus there is an increase inCD47, Creb11, and ITGA5 expression, and a decrease in proto-cadhedrin,cadhedrin, actin, and betaactin.

In addition, the abl family member abl2 (ARG) was significantlyassociated with disease progression; by contrast, abl1, which is bothexpressed from the normal chromosome 9 and the t(9;22) translocation,was not differentially expressed with progression. Advanced phasedisease was associated with deregulation of transcription factors,differentiation and apoptosis. Both components of the AP-1 transcriptioncomplex, Jun B and Fos, show decreased expression in progression. Inaddition, the Kupple-like zinc finger GLI2 is highly over-expressed inprogression. The block in differentiation may be facilitated by theup-regulation of MDFI, WT1, and AF1q, and the down regulation of GADD45.Apoptosis in blast cells appears to be inhibited by the over-expressionof Bcl2, DAP, and the decrease in MCL1 and Acinus. Progression was alsoassociated with alterations in normal protein chaperone and degradationprocesses, with a widespread decrease in the expression of HSP70 andDNAJ families of genes. In addition, proteosome components BMA1 PSME2,and TRIP12 were all significantly increased in advanced phase CML cases.

6.4. Identification of Progression-Specific Promoters

In order to examine if specific pathways were altered in progression,the progression and phase reporter gene sets were analyzed for aberrantexpression of genes possessing known promoter sequences. Aberrantregulation of several sets of promoter controlled genes was revealed(Table 6). The most statistically significantly set of genes showingaberrant control in progression where those that contained a MZFpromoter or a delta EF1 promoter sequence (p<10⁻¹⁵ and <10⁻¹¹,respectively; FIGS. 3 a and 3 b). Also significantly associated withprogression were genes bearing SPI-B, Yin Yang, and Ahr-ARNT promotersequences (all with p values <10⁻⁹).

6.5. Identification of Imatinib Responsiveness Reporter Genes

Gene expression profiles of patients who failed imatinib therapy wereanalyzed. A set of 21 cases of CML treated with the tyrosine kinaseinhibitor imatinib mesylate, including 9 patients who initially achieveda complete cytogenetic remission (CCR) on imatinib therapy, but thenrelapsed, most back into an apparent chronic phase by morphology; 3cases who had achieved a complete hematologic but no cytogeneticresponse; 3 late chronic phase patients before treatment with imatinib;and 6 cases of blast crisis was used. All but one of these the chronicphase patients who relapsed after a CCR had a point mutation in abl1,presumably abrogating imatinib activity (Table 7).

TABLE 7 Characteristics of cases treated with imatinib Phase of Diseaseat Phase of disease at CODE Case type initiation of imatinib time ofsample Cytogenetics Mutation(s)  2 Imatinib failure chronic relapsedchronic 100% Ph+; M244V NEW: t(1; 12) in all cells  4 Imatinib failurechronic relapsed chronic 100% Ph+ T315I  5 Imatinib failure chronicrelapsed chronic 80% Ph+ F359V  6 Imatinib failure chronic relapsedchronic 100% Ph+ M351T, F317L  8 Imatinib failure chronic relapsedchronic 100% Ph+ M351T 10 Imatinib failure chronic relapsed chronic 100%Ph+ E255K 11 Imatinib failure chronic post-allo relapsed chronic notavailable T315I BMT 12 Imatinib failure chronic relapsed chronic 100%Ph+ L248V 14 Imatinib failure chronic relapsed chronic 100% Ph+ M351T,H396R 15 Pre-imatinib chronic chronic pre-treatment 50% Ph+ nonetreatment 17 Pre-imatinib chronic chronic pre-treatment 100% Ph+ nonetreatment 18 Pre-imatinib chronic CHR; no cytogenetic 100% Ph+ nonetreatment response 19 Pre-imatinib chronic chronic pre-treatment 45%t(9; 13; 22); 50% none treatment t (9; 13; 22), −Y; 5% nl 21Pre-imatinib chronic CHR; no cytogenetic 100% Ph+ none treatmentresponse 22 (same pt as Pre-imatinib chronic CHR; no cytogenetic 100%Ph+ (3 of 18 none 13) treatment response with additional Ph) 23Pre-imatinib myeloid blast crisis pre-treatment MBC 100% Ph+ nonetreatment 24 Pre-imatinib myeloid blast crisis pre-treatment MBC 100%Ph+, t(2; 16) none treatment 25 Pre-imatinib myeloid blast crisispre-treatment MBC 100% Ph+, +8, iso none treatment 17q 26 Pre-imatinibmyeloid blast crisis not treated not available unknown treatment 27Pre-imatinib myeloid blast crisis relapsed MBC 100% Ph+ unknowntreatment 29 Pre-imatinib myeloid blast crisis relapsed MBC notavailable unknown treatment 29 Pre-imatinib myeloid blast crisisrelapsed MBC not available unknown treatment

FIG. 4 a shows the expression pattern of 15 cases of clinical chronicphase CML patients, 3 with longstanding chronic phase before imatinibtreatment, the other 12 who had initially a suboptimal response(achieving only a hematological response) or relapsed after an initialCCR. The association with the progression signature can be demonstratedby segregating all CML cases by the correlation of gene expressionsignature between the boundaries of “most chronic” and “most advanced”gene expression for all 3,000 genes in the phase reporter gene set (FIG.4 b). The majority of the poor response patients had gene expressionprofiles more consistent with advanced disease rather than chronicphase. Both cases with T315I mutations, which have been shown to haveespecially poor prognosis, have expression signatures more similar toadvanced disease than chronic phase. However, while these imatinibfailures shared much of the blast crisis signature, there were geneexpression features that were unique to these cases. FIG. 4 c comparesrelapsed imatinib cases against blast crisis cases. Several areas(boxed) indicate genes that are expressed in reverse direction in thesetwo states. Table 4 lists genes in the first box which are stronglyassociated with imatinib failure. Examples of genes unique to imatinibfailure are those of serine threonine kinases (CTRL, MAP21K14, CLK3),MAP kinase (MKNK2), and the tyrosine kinase oncogene FYN. The highestgenes over-expressed in imatinib resistant cases were TCF7 (a putativelyT cell specific transcription factor), two guanine nucleotide bindingproteins (GNAZ and GNG11), and the MAF oncogene.

6.6. Discussion

The biology and treatment of CML is dictated by the phase of disease,since the efficacy of all therapies (transplantation, interferon,imatinib) works best in chronic phase, and worse in accelerated phaseand blast crisis. Understanding the biology of progression providesclinical diagnostic markers of progression, and offer insights into newstrategies for treatment. The data presented in these examples suggestthat the progression of chronic phase CML to advanced phase CML is atwo-step process, with progression associated with a block ofdifferentiation and apoptosis, a shift towards turning on expression ofgenes involved in the nucleosome, while down-regulating histonetranscription. Moreover, progression is associated with alterations incell adhesion, and activation of alternative signaling pathways. Inaddition, it appears that relapse after initial successful treatmentwith imatinib may be associated with gene expression patterns similar toadvanced phase CML, suggesting that the process of progression persistsin a subpopulation of CML cells even in the background of apparentsuccessful therapy.

The demonstration that the gene expression pattern between acceleratedand blast phases are very similar suggests that the crucial steps inprogression are at the transition of chronic to accelerated phase,before obvious morphologic, cytogenetic or clinical evidence ofprogression. This has obvious clinical implications, since thesepatients might benefit from aggressive therapy. In addition, theobservation that gene signatures of blast crisis can be seen inaccelerated phase patients by cytogenetic criteria only, and blastcrisis cases in remission (both of which have low blast counts similarto patients with chronic phase disease), demonstrates two importantpoints. First, it points out the difficulty of correlating morphologywith the biology of the disease.

Secondly, the penetration of a progression gene expression signatureinto a “chronic phase” appearing bone marrow suggests that progressionis not merely an absolute block of differentiation, but that abnormalgene expression signals “leak” from the presumably immature blast crisisprecursors into more normal appearing differentiated cell. This iscritically important since it provides the basis for testing forprogression genes in unsorted bone marrow samples from “chronic phase”patients.

In addition, the finding that CML blasts share a gene expression profilewith normal CD34+ cells has important biological considerations(Passegue et al., 2003, Proc Natl Acad Sci USA 100 Suppl 1:11842).First, it implies that there may be a limited number of novel pathwaysactive in CML blasts. This finding is obviously important (andencouraging) in the era of targeted therapeutics. It also may explainthe relative resistance of blast crisis CML to chemotherapy. Normalhematopoetic stem cells are remarkably resistant to chemotherapy, andthus in AML and ALL, with remission comes the return of normalhematopoiesis. Remission is rare in blast crisis CML, perhaps becausethe blast cells are similarly resistant to chemotherapy as their normalcounterpart.

Bcr-Ab1 has a wholesale range of biological activities. Critical in thetransformation process is the activation of the Ras/MAPK pathways, whichhas broad effects on changes in cell adhesion (through Rho),proliferation (MAPK pathway), and apoptosis (through Akt) (Faderl etal., 1999, N Engl J Med 341:164; Ren, 2002, Oncogene 21:8629). Theefficacy of imatinib works through the blockade of these effects.

Imatinib works poorly on advanced phase disease, and it may be becausethese tumors are less reliant on the pathways that imatinib blocks thanchronic phase disease. Thus, it was found that the MAPK pathway wasrelatively under-expressed in advanced disease compared to chronicphase, but other signaling pathways, including those involving cytokines(IL3RA, SOCS2), alternative ras pathways (Rras2), and those involved incell adhesion (B-catenin/WNT) were activated. The activation of thesepathways may allow progression even in the face of therapeutic blockadeof Bcr-Ab1 activated pathways. In addition, abl2 (Ab1 related gene, orARG) is also upregulated in progresson. As opposed to abl1 (which is anuclear protein until involved in the chimeric Bcr-Ab1 protein, at whichtime it migrates to the cytoplasm), ARG is a cytoplasmic protein (Kruhet al., 1990, Proc Natl Acad Sci USA 87:5802). The signaling targets ofARG are unknown, and although broadly expressed in tissue, its onlyknown functional role apparent from knockout mouse models appears to bein the nervous system (Koleske et al., 1998, Neuron 21:1259; Perego etal., 1991, Oncogene 6:1899). ARG has been associated with myeloidleukemia in the contest of TEL/ARG translocations (Cazzaniga et al.,1999, Blood 94:4370; Iijima et al., 2000, Blood 95:2126). ARG sharesover 90% homology of its tyrosine kinase domain with abl1, and ARGtyrosine kinase activity is inhibited by imatinib at similar drugconcentrations (Kruh et al., 1990, Proc Natl Acad Sci USA 87:5802; Okudaet al., 2001, Blood 97:2440). However, given that Bcr-ABL amplificationis considered to play a role in imatinib resistance (le Coutre et al.2000, Blood 95:1758; Weisberg et al., 2000, Blood 95:3498), ARGover-expression in blast crisis could theoretically contribute to therelative resistance to imatinib found with progressive disease.

Two recent observations on the molecular biology of progression in CMLare relevant to this study. First, activation of the beta-cateninpathway was observed in primary cell samples from patients with CML(Jamieson et al., 2004, N Engl J Med 351:657). Secondly, it was recentlyobserved that mice deficient in Jun B develop a disease much like CML(Passegue et al., 2004, Cell 119:431). The data in these examplescomplement these findings, as we found broad dysregulation ofWNT/beta-catenin pathway as well as decreased Jun B expression. A linkbetween these pathways may be the gene MDFI (Imfa), an inhibitor ofmyogenic basic H-L-H transcription factors 4. MDFI interacts with axin,which is involved in binding and modulating free beta-catenin. Thus anincrease in MDFI would effectively allow for more free beta-catenin tomigrate to the nucleus, where it causes gene activation (Nelson et al.,2004, Science 303:1483). An increase in MDFI could also decrease theaxinmediated activation of Jun (Kusano et al., 2002, Mol Cell Biol22:6393). Thus, MDFI may play a central role in progression by bothinfluencing the beta-catenin and Jun B pathways. Moreover, the fact thatboth Jun B and Fos were down-regulated in progression suggests thatthere may be a wholesale deregulation in AP-1 targets, which could havebroad functional affects on differentiation, apoptosis, and cell cyclecontrol (Hess et al., 2004, J Cell Sci 117:5965).

The analysis suggests that genes controlled by MZF1 and delta EF1 may beparticularly important in progression. MZF1 is a member of the Kruppelfamily of zinc finger proteins, and was originally cloned from a cDNAlibrary from a blast crisis CML patient (Hromas et al., 1991, J BiolChem 266:14183). MZF1 appears to play a critical role in hematopoeticstem cell differentiation, including modulation of CD34 and c-mybexpression (Gaboli et al., 2001, Genes Dev 15:1625; Perrotti et al.,1995, Mol Cell Biol 15:6075). MZF1 −/− knock-out mice display anincrease in hemapoetic progenitor proliferation which continues inlong-term culture conditions (Gaboli et al., 2001, Genes Dev 15:1625).These data support the findings found in our human studies describedabout that MZF1 deregulation may disrupt normal differentiation,promoting the progression to advanced disease. Delta EF1 is related tothe Smad zinc finger proteins that play an important role in TGFbetagene regulation. Delta EF1 has been shown to compete with basichelix-loop-helix activators, and is implicated in modulation of MyoDregulated pathways (Funahashi et al., 1993, Development 119:433; Sekidoet al., 1994, Mol Cell Biol 14:5692). It is not known if delta EF1directly influences MDFI expression.

Of note is that both MZF1 and delta EF1 have been shown to influencecadherin expression (Guaita et al., 2002, J Biol Chem 277:39209; Le etal., 2005, Exp Cell Res 302:129; Miyoshi et al., 2004, Br J Cancer90:1265). Thus, the further study of the control of MZF1 and delta EF1may be particularly fruitful in understanding the molecular mechanismsof CML progression. Given that efficacy of treatment in CML (be it withinterferon, imatinib, or transplantation) is so intimately associatedwith phase of disease, those patients who fail therapy in chronic phasemay have genetic features of advanced phase invisible to routinepathological and cytogenetic exam. Imatinib failures are a reasonablesetting to explore this possibility. While imatinib can causecytogenetic remissions in the majority of chronic phase cases, treatmentfailure, especially secondary to point mutations, is an increasinglyimportant problem. It has previously been demonstrated that theprobability of developing a point mutation depends largely on the timefrom diagnosis to initiation of therapy (Branford et al., 2003, Blood102:276). This finding implies that the genetic mechanisms that lead topoint mutations are relentless, and therefore the treatment of “late”chronic phase patients (i.e., >1 year from diagnosis) may be underminedby genetic changes that have already occurred. Branford et al.demonstrated that patients who developed point mutations had a very pooroutcome, with approximately half dying within a year of relapse(Branford et al., 2003, Blood 102:276). These observations are inkeeping with the demonstration in these examples that many imatinibfailures have gene expression changes similar to advanced disease,despite their benign pathological appearance. Thus, resistance toimatinib may be ameliorated by either targeting pathways of progression(beta-catenin, JunB/Fos, etc.), or by targeting pathways specificallyfound activated in imatinib resistance cases (alternative kinases,protein transporters).

Several of the genes found in the progression set might serve as earlymarkers of progression in diagnostic assays, and may serve astherapeutic targets, as well. For example, PRAME (PreferentiallyExpressed Antigen of Melanoma) was originally identified as a tumorantigen recognized by cytotoxic T-cells against a melanoma surfaceantigen (Matsushita et al., 2001, Br J Haematol 112:916, 2001; van Barenet al., 1998, Br J Haematol 102:1376). Like similar antigens MAGE, BAGE,and GAGE, which are expressed in some solid tumors; unlike these otherantigens, however, PRAME has been found to be overexpressed in over 25%of leukemia, and has been found to be induced by Bcr-Abl in CML celllines (Watari et al., 2000, FEBS Lett 466:367). Indeed, PRAMEover-expression has been described as one of the few features thatcharacterize the transient myeloproliferative syndrome of Down'ssyndrome from the progressive acute megakaryoblastic leukemia found inthat disorder (McElwaine et al., 2004, Br J Haematol 125:729). While thefunction of PRAME is still unknown, its expression on the cell surfacemight be amenable to flow cytometry assays, as well as a target forimmunologic (vaccine or cell-based) therapy. CD47, an integrin-likeprotein, is another potential diagnostic target discovered in ouranalysis of progression (Motegi et al., 2003, Embo J 22:2634; Okazawa etal., 2005, J Immunol 174:2004). In addition, the demonstration ofaberrant regulation of alternative signaling pathways (FLT3; Rras2;beta-catenin. SOCS2), proteosomes, and chaperone proteins suggest thatthe targeting of several novel pathways may be needed in the treatmentof advanced CML.

Compared to other types of leukemia, there have been few papersexploring the use of microarrays on the biology of CML. In sum, 23patients of various stages have been studied, 10 on unsorted samples, 13from AC133+ isolated cells. It is difficult to make a direct comparisonof these studies and ours, given the different types of samplesobtained, the difference in the array platforms (these studies usedplatforms examining 3,000-5,000 genes, compared to ˜24,000 genes in thiscurrent study). In general, however, the functional changes ofprogression, e.g., changes in differentiation, apoptosis, and celladhesion, remained as common themes across the study. In contrast to onestudy, no significant differences in signatures obtained from bonemarrow and peripheral blood (FIG. 7) were found, which may be importantin future prospective studies of this disease in patients.

These findings have the potential to influence therapy of CML. Patientswho present with gene expression patterns suggestive of advanced phasedisease might benefit to move straight to transplantation if a donorexists, or if not, other investigation therapies. Moreover, PCR assaysof individual genes (or small sets of genes) may be used to monitorpatients early in the course of imatinib therapy for signs ofprogression to advanced disease. Microarray studies of large cohorts ofpatients treated with imatinib will likely identify gene patternsindicative of response that can be used immediately at diagnosis totailor therapy.

6.7. Materials and Methods

Patient samples. All samples were obtained under the auspices ofinstitutional review board approve protocols. Samples came from theFHCRC, the Southwest Oncology Group (SWOG) Myeloid Repository, theUniversity of Oregon Health Sciences Center, the University ofCalifornia, Los Angeles, or the University of Chicago. RNA extractionwas either performed immediately, or in the case of samples stored in aliquid nitrogen repository, after thawing. All RNA samples were qualitytested by analysis of ribosomal RNA peaks using an ABI Bioalyzer. Thedefinition of chronic, accelerated and blast crisis was based on thecriteria of Sokal (Sokal et al., 1984, Blood 63:789).

Amplification, labeling, and hybridization. The procedures of RNAamplification, labeling, and the hybridization to arrays, as well as thespecifics of the array platforms, has been previously published (Hugheset al., 2001, Nat Biotechnol 19:342).

Analytic Methods and Results. Each individual sample was hybridized to apool of chronic phase samples. The log10 (Ratio) of intensity ofindividual samples to the pool were used for the subsequent analysis.Before selecting features by ANOVA, 25,000 genes on the array were firstscreened for evidence of differential regulation by requiring P-value ofregulation <1% in more than 3 experiments. Where P-value of regulationis based on the platform error model. Features differentiatingprogression stages were selected by ANOVA test.

Functional annotation of gene lists. Genes represented on the microarraywere annotated by assignment to GO Biological Process or MolecularFunction categories (at the web address www.ebi.ac.uk/GOA/), or to KEGGpathways (at the web address www.genome.jp/kegg/pathway.html). Genelists (input sets) were queried for enrichment of members of specificfunctional classes or pathways relative to the background frequency. Thesignificance (P-value) of enrichment was computed using thehypergeometric probability distribution. Reported in each case are thenumbers of genes in the input set (input gene count), number of genes ina particular category or pathway in the input set (overlap gene count),number of genes in a particular category among all genes present on thearray (set gene count). The total number of unique genes on the array is24132.

Methods to common promote site analysis. The common promoter sites werebased on the predictions derived from the database (oPOSSUM) byWasserman et al. (www.cisreg.ca). The hypergeometric P-value forenrichment of a particular binding site was computed by comparing thenumber of genes with the binding site from a signature gene set to thatfrom a background set (i.e., all genes represented on the microarray).

Controls. We compared the genes found associated with progression to thegenes found significantly over- and under-expressed with prolonged“transit time” from sample acquisition to RNA processing (Radich et al.,2004, Genomics 83:980). There gene signatures of the two data sets weredifferent, excluding this artifact as contributing significantly to theprogression gene set.

Lastly, we compared gene expression signatures from the sitescontributing samples to confirm that there were no site-signaturesconfounding the analysis. We found no evidence of site-specificsignatures.

As some samples of blast crisis came from peripheral blood rather thanbone marrow, we compared three samples in which simultaneous sampleswere available from bone marrow and peripheral blood. Gene expressionwas extremely well correlated (r=0.97 to 0.99; FIG. 7).

TABLE 8 The phase reporter genes SEQ PROBE SEQ SUBS GENE DESCRIPTIONSP_XREF_KEYWORD_LIST ID NO. ID NO. AB002301 KIAA0303 KIAA0303 proteinHypothetical protein, ATP-binding, 1 3969 Kinase,Serine/threonine-protein kinase, Transferase AB002313 PLXNB2 plexin B2Hypothetical protein 2 3970 AB002314 KIAA0316 KIAA0316 gene Hypotheticalprotein 3 3971 product AB002331 DATF1 death associated Apoptosis,Nuclear protein, Zinc- 4 3972 transcription factor 1 finger, Alternativesplicing AB002336 EPB41L1 erythrocyte Hypothetical protein, Structural 53973 membrane protein protein, Cytoskeleton, Actin-binding band 4.1-like1 AB002337 KIAA0339 KIAA0339 gene Hypothetical protein 6 3974 productAB002354 KIAA0356 pleckstrin homology Hypothetical protein 7 3975 domaincontaining, family M (with RUN domain) member 1 AB002359 PFASphosphoribosylformylglycinamidine Purine biosynthesis, Ligase, ATP- 83976 synthase (FGAR binding, Glutamine amidotransferase)amidotransferase, Hypothetical protein AB002360 MCF2L MCF.2 cell lineHypothetical protein, Guanine- 9 3977 derived transforming nucleotidereleasing factor, Proto- sequence-like oncogene AB002366 KIAA0368KIAA0368 Hypothetical protein 10 3978 AB002368 XPO6 exportin 6Hypothetical protein 11 3979 AB002369 MTMR3 myotubularin relatedHydrolase, Zinc-finger, Alternative 12 3980 protein 3 splicing,Hypothetical protein AB002373 KIAA0375 RUN and SH3 Hypothetical protein,SH3 domain 13 3981 domain containing 2 AB002377 KIAA0379 ankyrin repeatHypothetical protein, Repeat, ANK 14 3982 domain 28 repeat AB002379DAAM2 dishevelled Coiled coil, Alternative splicing 15 3983 associatedactivator of morphogenesis 2 AB004857 SLC11A2 solute carrier familyTransport, Iron transport, 16 3984 11 (proton-coupled Transmembrane,Glycoprotein, divalent metal ion Alternative splicing, Polymorphismtransporters), member 2 AB006622 KIAA0284 KIAA0284 Hypothetical protein17 3985 AB007855 TIX1 zinc fingers and DNA-binding, Homeobox, Nuclear 183986 homeoboxes 3 protein, Zinc-finger, Metal-binding, Repeat AB007863PIP3-E phosphoinositide- Hypothetical protein 19 3987 binding proteinPIP3-E AB007864 KIAA0404 KIAA0404 protein Hypothetical protein,Metal-binding, 20 3988 Oxidoreductase, Zinc AB007888 MBNL1muscleblind-like Hypothetical protein, Zinc-finger, 21 3989 (Drosophila)Repeat, Nuclear protein, RNA- binding, Alternative splicing AB007902AUTS2 autism susceptibility Chromosomal translocation, 22 3990 candidate2 Polymorphism, Alternative splicing AB007915 KIAA0446 KIAA0446 geneHypothetical protein 23 3991 product AB007931 RBAF600 retinoblastoma-Hypothetical protein 24 3992 associated factor 600 AB007941 KIAA0472dusty protein kinase ATP-binding, Transferase, 25 3993 Hypotheticalprotein, Kinase, Serine/threonine-protein kinase AB007958 KIAA0489KIAA0792 gene Hypothetical protein 26 3994 product AB007962 KIAA0493KIAA0493 protein 27 3995 AB007965 CYHR1 MRNA, chromosome 28 3996 1specific transcript KIAA0496. AB007972 PPP1R12B protein phosphatase ANKrepeat, Myosin, Repeat 29 3997 1, regulatory (inhibitor) subunit 12BAB011093 P114-RHO- rho/rac guanine Hypothetical protein 30 3998 GEFnucleotide exchange factor (GEF) 18 AB011105 LAMA5 laminin, alpha 5Laminin EGF-like domain, Signal, 31 3999 Glycoprotein, Basementmembrane, Extracellular matrix, Coiled coil, Cell adhesion, RepeatAB011112 KIAA0540 KIAA0540 protein Hypothetical protein, Repeat, WD 324000 repeat AB011114 KIAA0542 KIAA0542 gene Hypothetical protein 33 4001product AB011133 KIAA0561 microtubule Hypothetical protein, ATP-binding,34 4002 associated Kinase, Serine/threonine-protein serine/threoninekinase, Transferase kinase 3 AB011136 KIAA0564 KIAA0564 proteinHypothetical protein, ATP-binding 35 4003 AB011153 PLCB1 phospholipaseC, Hydrolase, Lipid degradation, 36 4004 beta 1 Transducer,Phosphorylation, (phosphoinositide- Calcium, Alternative splicingspecific) AB011154 RAB1A KIAA0582 protein Hypothetical protein 37 4005AB011157 PTDSR phosphatidylserine Hypothetical protein, Receptor 38 4006receptor AB011167 KIAA0595 peroxisome Hypothetical protein 39 4007proliferative activated receptor, gamma, coactivator- related 1 AB011171KIAA0599 KIAA0599 Hypothetical protein, Plasmid 40 4008 AB011173KIAA0601 amine oxidase Hypothetical protein 41 4009 (flavin containing)domain 2 AB011542 EGFL5 EGF-like-domain, Laminin EGF-like domain 42 4010multiple 5 AB012692 CAC-1 beta-casein-like Hypothetical protein 43 4011protein AB014516 MECT1 Homo sapiens Transcription regulation, DNA- 444012 mRNA for KIAA0616 binding, Activator, Nuclear protein, protein,partial cds. Phosphorylation, Cell cycle, Alternative splicing,3D-structure, Polymorphism, Hypothetical protein AB014520 PLXND1 plexinD1 Hypothetical protein 45 4013 AB014538 KIAA0638 pleckstrin homology-Hypothetical protein 46 4014 like domain, family B, member 1 AB014543KIAA0643 KIAA0643 protein Hypothetical protein 47 4015 AB014548 KIAA0648KIAA0648 protein Hypothetical protein 48 4016 AB014557 KIAA0657 KIAA0657protein Hypothetical protein, 49 4017 Immunoglobulin domain AB014558CRY2 cryptochrome 2 Lyase, Hypothetical protein 50 4018(photolyase-like) AB014564 KIAA0664 KIAA0664 protein Hypotheticalprotein, Initiation factor, 51 4019 Protein biosynthesis AB014566 DAAM1dishevelled Coiled coil, Alternative splicing 52 4020 associatedactivator of morphogenesis 1 AB014567 TIP120B TBP-interactingHypothetical protein 53 4021 protein AB014568 UNC84B unc-84 homolog BTransmembrane, Nuclear protein, 54 4022 (C. elegans) Coiled coilAB014574 KIAA0674 KIAA0674 protein Hypothetical protein 55 4023 AB014578KIAA0678 RME8 protein Hypothetical protein 56 4024 AB014589 CSTF2Tcleavage stimulation Hypothetical protein 57 4025 factor, 3′ pre-RNA,subunit 2, 64 kDa, tau variant AB014597 GTAR ankyrin repeat Hypotheticalprotein, ANK repeat, 58 4026 domain 17 Repeat AB014600 SIN3B SIN3homolog B, Transcription regulation, Repressor, 59 4027 transcriptionalRepeat, Nuclear protein regulator (yeast) AB014604 OSBPL3 oxysterolbinding Lipid transport, Transport, 60 4028 protein-like 3 Alternativesplicing AB015330 DKFZP761I2123 hypothetical protein Hypotheticalprotein 61 4029 DKFZp761I2123 AB015343 HRIHFB2122 Tara-like proteinCytoskeleton, Actin-binding, Coiled 62 4030 coil, Nuclear proteinAB018268 KIAA0725 SAM, WWE and Hypothetical protein 63 4031 DDHD domaincontaining 1 AB018325 CENTD2 centaurin, delta 2 GTPase activation,Repeat, Zinc- 64 4032 finger, Alternative splicing AB018339 SYNE1spectrin repeat Structural protein, Cytoskeleton, 65 4033 containing,nuclear Actin-binding, Coiled coil, envelope 1 Transmembrane, Repeat,Alternative splicing, Polymorphism AB018348 PCNX pecanex homologTransmembrane, Glycoprotein, 66 4034 (Drosophila) Alternative splicingAB018353 UNC84A unc-84 homolog A Transmembrane, Nuclear protein, 67 4035(C. elegans) Coiled coil, Alternative splicing AB020627 KIAA0820 dynaminfamily Hydrolase, Motor protein, GTP- 68 4036 member binding,Microtubule, Multigene family, Endocytosis AB020636 TIP120ATBP-interacting Hypothetical protein 69 4037 protein AB020637 KIAA0830KIAA0830 protein Hypothetical protein 70 4038 AB020644 FACL6 acyl-CoAsynthetase Ligase, Fatty acid metabolism, 71 4039 long-chain familyMagnesium, Multigene family, member 6 Alternative splicing, Chromosomaltranslocation, Hypothetical protein AB020649 KIAA0842 pleckstrinhomology Hypothetical protein 72 4040 domain containing, family M (withRUN domain) member 2 AB020673 MYH11 myosin, heavy Myosin, Muscleprotein, Coiled coil, 73 4041 polypeptide 11, Thick filament,Actin-binding, smooth muscle Calmodulin-binding, ATP-binding,Methylation, Multigene family, Proto- oncogene, Chromosomaltranslocation AB020684 KIAA0877 KIAA0877 protein Hypothetical protein 744042 AB020691 KIAA0884 GTPase activating Hypothetical protein 75 4043RANGAP domain- like 1 AB020695 KIAA0888 KIAA0888 protein Hypotheticalprotein 76 4044 AB020698 USP19 ubiquitin specific Protease, Ublconjugation pathway, 77 4045 protease 19 Hydrolase, Thiol protease,Multigene family, Zinc-finger, Metal-binding AB020703 DD5 progestininduced Ubl conjugation pathway, Ligase, 78 4046 protein Nuclearprotein, 3D-structure AB020704 PPFIA4 protein tyrosine Hypotheticalprotein 79 4047 phosphatase, receptor type, f polypeptide (PTPRF),interacting protein (liprin), alpha 4 AB023152 KIAA0935 mannosidasealpha Hydrolase, Glycosidase, Signal, 80 4048 class 2B member 2Glycoprotein, Hypothetical protein AB023154 KIAA0937 macrophageHypothetical protein, Metal-binding, 81 4049 expressed gene 1 Zinc,Zinc-finger AB023156 SLC9A8 solute carrier family Hypothetical protein82 4050 9 (sodium/hydrogen exchanger), isoform 8 AB023164 KIAA0947KIAA0947 protein Hypothetical protein 83 4051 AB023210 WDFY3 WD repeatand Hypothetical protein, Repeat, WD 84 4052 FYVE domain repeatcontaining 3 AB023211 PADI2 peptidyl arginine Hydrolase,Calcium-binding, 85 4053 deiminase, type II Multigene family AB023212PCNX pecanex homolog Transmembrane, Glycoprotein, 86 4054 (Drosophila)Alternative splicing AB023216 KIAA0999 KIAA0999 protein Hypotheticalprotein, ATP-binding, 87 4055 Kinase, Serine/threonine-protein kinase,Transferase AB023230 KIAA1013 GRP1-binding Hypothetical protein,Cytoskeleton 88 4056 protein GRSP1 AB023233 CHDC1 calponin homologyHypothetical protein, Leucine-rich 89 4057 (CH) domain repeat, Repeatcontaining 1 AB025254 PCTAIRE2BP tudor repeat Hypothetical protein 904058 associator with PCTAIRE 2 AB026054 ZNF179 zinc finger proteinZinc-finger 91 4059 179 AB026436 DUSP10 dual specificity Hydrolase,Nuclear protein, 92 4060 phosphatase 10 Hypothetical protein AB028972KIAA1049 KIAA1049 protein Hypothetical protein 93 4061 AB028978 KIAA1055KIAA1055 protein Hypothetical protein 94 4062 AB028980 USP24 ubiquitinspecific Hypothetical protein, Ubl conjugation 95 4063 protease 24pathway, Hydrolase, Thiol protease, Multigene family AB028986 USP22ubiquitin specific Hypothetical protein, Protease, Ubl 96 4064 protease22 conjugation pathway, Hydrolase, Thiol protease, Multigene familyAB028989 MAPK8IP3 mitogen-activated Phosphorylation, Coiled coil 97 4065protein kinase 8 interacting protein 3 AB028994 AMOT angiomotinHypothetical protein 98 4066 AB029030 KIAA1107 KIAA1107 proteinHypothetical protein 99 4067 AB029032 FLJ21404 hypothetical proteinHypothetical protein 100 4068 KIAA1109 AB029041 KIAA1118 likely orthologof Hypothetical protein 101 4069 mouse 5-azacytidine induced gene 1AB032952 KIAA1126 KIAA1126 protein Hypothetical protein 102 4070AB032965 CASKIN2 CASK interacting Hypothetical protein, ANK repeat, 1034071 protein 2 Repeat AB032973 LCHN LCHN protein Hypothetical protein104 4072 AB032976 P66 transcription Hypothetical protein 105 4073repressor p66 beta component of the MeCP1 complex AB032993 GRIPAP1 GRIP1associated Hypothetical protein 106 4074 protein 1 AB033009 KIAA1183KIAA1183 protein Hypothetical protein 107 4075 AB033037 KIAA1211KIAA1211 protein Hypothetical protein 108 4076 AB033050 RAI17 retinoicacid induced Hypothetical protein 109 4077 17 AB033053 ZNF295 zincfinger protein Transcription regulation, DNA- 110 4078 295 binding,Zinc-finger, Metal-binding, Nuclear protein, Repeat AB033055 KIAA1229KIAA1229 protein Hypothetical protein 111 4079 AB033068 FZR1 Fzr1protein Hypothetical protein, Ubl conjugation 112 4080 pathway, Cellcycle, Cell division, Mitosis, Repeat, WD repeat, Phosphorylation,Alternative splicing AB033070 KIAA1244 KIAA1244 Hypothetical protein 1134081 AB033073 KIAA1247 sulfatase 2 Hydrolase, Signal, Glycoprotein, 1144082 Endoplasmic reticulum, Golgi stack AB033085 KIAA1259 hypotheticalprotein Hypothetical protein, ATP-binding, 115 4083 KIAA1259 Helicase,Hydrolase AB033087 TLE4 transducin-like Transcription regulation,Repressor, 116 4084 enhancer of split 4 Nuclear protein, Repeat, WDrepeat, (E(sp1) homolog, Phosphorylation, Wnt signaling Drosophila)pathway AB033091 KIAA1265 solute carrier family Hypothetical protein 1174085 39 (zinc transporter), member 10 AB033092 MTA3 metastasisHypothetical protein, Zinc-finger, 118 4086 associated family, Nuclearprotein, Alternative splicing member 3 AB033100 KIAA1274 KIAA protein(similar Hypothetical protein 119 4087 to mouse paladin) AB033108 KCNH3potassium voltage- Hypothetical protein, Transport, Ion 120 4088 gatedchannel, transport, Ionic channel, Voltage- subfamily H (eag- gatedchannel, Potassium channel, related), member 3 Potassium transport,Transmembrane, Glycoprotein, Multigene family AB033112 BRPF3 bromodomainand Hypothetical protein, Zinc-finger, 121 4089 PHD finger Bromodomaincontaining, 3 AB033118 ZDHHC8 zinc finger, DHHC Transmembrane,Zinc-finger, 122 4090 domain containing 8 Hypothetical protein AB037716KIAA1295 KIAA1295 protein Hypothetical protein, SH3 domain 123 4091AB037720 SH2B SH2-B homolog Hypothetical protein 124 4092 AB037721STARD9 START domain Hypothetical protein 125 4093 containing 9 AB037722KIAA1301 NEDD4-related E3 Hypothetical protein 126 4094 ubiquitin ligaseNEDL2 AB037729 RALGDS ral guanine Guanine-nucleotide releasing factor,127 4095 nucleotide 3D-structure, Hypothetical protein dissociationstimulator AB037749 KIAA1328 KIAA1328 protein Hypothetical protein 1284096 AB037757 KIAA1336 WD repeat domain Hypothetical protein, Repeat, WD129 4097 35 repeat AB037760 ZNF398 zinc finger protein Transcriptionregulation, Activator, 130 4098 398 DNA-binding, Zinc-finger, Metal-binding, Nuclear protein, Repeat, Alternative splicing AB037771 KIAA1350ubiquitin specific Hypothetical protein 131 4099 protease 53 AB037787NLGN2 neuroligin 2 Cell adhesion, Glycoprotein, Signal, 132 4100Transmembrane AB037795 KIAA1374 KIAA1374 protein Hypothetical protein,Repeat, WD 133 4101 repeat AB037802 COG1 component of Transport, Proteintransport, Golgi 134 4102 oligomeric golgi stack, Membrane complex 1AB037813 DKFZp762K222 hypothetical protein Hypothetical protein 135 4103DKFZp762K222 AB037814 KIAA1393 KIAA1393 Hypothetical protein 136 4104AB037836 PRex1 phosphatidylinositol Guanine-nucleotide releasing factor,137 4105 3,4,5-trisphosphate- Repeat, Alternative splicing dependent RACexchanger 1 AB037845 ARHGAP10 Rho GTPase Hypothetical protein 138 4106activating protein 21 AB037851 KIAA1430 KIAA1430 protein Hypotheticalprotein 139 4107 AB037855 KIAA1434 hypothetical protein Hypotheticalprotein 140 4108 KIAA1434 AB037859 MKL1 megakaryoblastic Transcriptionregulation, Nuclear 141 4109 leukemia protein, Coiled coil, Repeat,(translocation) 1 Chromosomal translocation, Proto- oncogene AB037860NFIA nuclear factor I/A Activator, DNA replication, DNA- 142 4110binding, Nuclear protein, Transcription, Transcription regulation,Multigene family AB037861 DKFZP586J0619 DKFZP586J0619 Hypotheticalprotein 143 4111 protein AB040881 KIF1B kinesin family Hypotheticalprotein, Motor protein, 144 4112 member 1B Microtubule, ATP-binding,Coiled coil, Mitochondrion, Alternative splicing, Disease mutation,Charcot- Marie-Tooth disease AB040900 KIAA1467 KIAA1467 proteinHypothetical protein 145 4113 AB040907 KIAA1474 zinc finger proteinHypothetical protein, Metal-binding, 146 4114 537 Zinc, Zinc-fingerAB040908 VPS18 vacuolar protein Transport, Protein transport, 147 4115sorting protein 18 Membrane, Zinc-finger, Coiled coil, Alternativesplicing AB040917 KIAA1484 leucine rich repeat Hypothetical protein, 1484116 and fibronectin type Immunoglobulin domain III domain containing 1AB040930 LRRN1 leucine rich repeat Hypothetical protein, 149 4117neuronal 1 Immunoglobulin domain AB040942 KIAA1509 KIAA1509 Hypotheticalprotein, Plasmid 150 4118 AB040955 KIAA1522 KIAA1522 proteinHypothetical protein 151 4119 AB040960 FLJ22670 lymphocyte alpha-Hypothetical protein, Kinase 152 4120 kinase AB040961 DTX2 deltexhomolog 2 Nuclear protein, Repeat, Metal- 153 4121 (Drosophila) binding,Zinc, Zinc-finger, Alternative splicing, Polymorphism AB040968 HCN3hyperpolarization Transport, Ion transport, Ionic 154 4122 activatedcyclic channel, Voltage-gated channel, nucleotide-gated Potassiumchannel, Potassium, potassium channel 3 Potassium transport, Sodiumtransport, cAMP, cAMP-binding, Transmembrane, Glycoprotein, Sodiumchannel AB040969 KIAA1536 KIAA1536 protein Hypothetical protein 155 4123AB040972 FLJ11560 Homo sapiens Hypothetical protein 156 4124 mRNA forKIAA1539 protein, partial cds. AF000560 hypothetical proteinMetal-binding, Zinc, Zinc-finger 157 4125 LOC126208 AF007217 TRIP11thyroid hormone Antigen, Golgi stack, Coiled coil, 158 4126 receptorinteractor Chromosomal translocation, 11 Hypothetical protein AF011757S100A12 S100 calcium Calcium-binding, Zinc, Metal-binding 159 4127binding protein A12 (calgranulin C) AF016267 TNFRSF10C tumor necrosisfactor Receptor, Apoptosis, Glycoprotein, 160 4128 receptor superfamily,Repeat, GPI-anchor, Signal, member 10c, decoy Lipoprotein without anintracellular domain AF016495 AQP9 aquaporin 9 Transport, Repeat,Transmembrane 161 4129 AF017433 ZNF213 zinc finger protein Transcriptionregulation, DNA- 162 4130 213 binding, Zinc-finger, Metal-binding,Nuclear protein, Repeat AF026816 ITPA inosine Hydrolase, Nucleotidemetabolism, 163 4131 triphosphatase Disease mutation (nucleosidetriphosphate pyrophosphatase) AF031166 SRP46 Splicing factor, 164 4132arginine/serine-rich, 46 kD AF034803 PPFIBP2 PTPRF interacting Receptor,Hypothetical protein 165 4133 protein, binding protein 2 (liprin beta 2)AF035307 plexin C1 166 4134 AF038193 ADP-ribosylation GTP-binding,Multigene family, 167 4135 factor-like 3 Polymorphism AF038535 SYT7synaptotagmin VII Transmembrane, Repeat, Synapse 168 4136 AF038554 DENRdensity-regulated Hypothetical protein 169 4137 protein AF043469 NXPH4serine Transferase, Methyltransferase, 170 4138 hydroxymethyltransferase2 Pyridoxal phosphate, One-carbon (mitochondrial) metabolism,Mitochondrion, Transit peptide, Glycoprotein, Repeat, Signal,Hypothetical protein AF045229 RGS10 regulator of G- Signal transductioninhibitor, 171 4139 protein signalling 10 Lipoprotein, Palmitate,Alternative splicing, Polymorphism AF049140 UBE2V2 ubiquitin-conjugatingLigase, Ubl conjugation pathway, 172 4140 enzyme E2 variant 2 Vitamin DAF052093 NJMU-R1 protein kinase Njmu- 173 4141 R1 AF052117 chloridechannel 4 Ionic channel, Ion transport, Chloride 174 4142 channel,Chloride, Voltage-gated channel, Transmembrane, CBS domain, RepeatAF052159 protein tyrosine 175 4143 phosphatase-like (proline instead ofcatalytic arginine), member b AF052167 MRS2L MRS2-like, Signal,Hypothetical protein 176 4144 magnesium homeostasis factor (S.cerevisiae) AF052169 LOC115207 potassium channel Hypothetical protein177 4145 tetramerisation domain containing 12 AF052181 epimorphin 1784146 AF055006 SEC6 SEC6-like 1 (S. cerevisiae) Hypothetical protein,Exocytosis, 179 4147 Transport, Protein transport, Coiled coil,Alternative splicing AF055012 TGIF2 TGFB-induced factor DNA-binding,Homeobox, 180 4148 2 (TALE family Transcription regulation, Nuclearhomeobox) protein, Phosphorylation AF055016 C13orf1 chromosome 13Hypothetical protein 181 4149 open reading frame 1 AF055019 homeodomainTransferase, Serine/threonine- 182 4150 interacting protein proteinkinase, ATP-binding, Nuclear kinase 2 protein, Alternative splicingAF055029 hypothetical protein 183 4151 LOC151162 AF055270 SFRS7 Homosapiens heat- Nuclear protein, RNA-binding, 184 4152 shock suppressedmRNA splicing, Alternative splicing, protein 1 (HSSG1) Phosphorylation,Repeat, Zinc- mRNA, complete finger, Hypothetical protein cds. AF059531PRMT3 protein arginine N- Hypothetical protein, Transferase, 185 4153methyltransferase 3 Methyltransferase, Zinc-finger AF062341 CTNND1catenin (cadherin- Cytoskeleton, Structural protein, 186 4154 associatedprotein), Phosphorylation, Repeat, Cell delta 1 adhesion, Coiled coil,Nuclear protein, Alternative splicing AF063020 PSIP2 PC4 and SFRS1Receptor 187 4155 interacting protein 1 AF067972 DNMT3A DNA(cytosine-5-)- Methyltransferase, Transferase, 188 4156methyltransferase 3 Zinc-finger, Metal-binding, Nuclear alpha protein,Hypothetical protein AF068296 MRPS35 mitochondrial Hypothetical protein,Ribosomal 189 4157 ribosomal protein protein, Mitochondrion S35 AF070587Clone 24741 mRNA 190 4158 sequence AF070643 LOC55977 intraflagellar 1914159 transport protein IFT20 AF072810 BAZ1B bromodomain Transcriptionregulation, 192 4160 adjacent to zinc Bromodomain, Zinc-finger, Coiledfinger domain, 1B coil, Nuclear protein, Alternative splicing,Williams-Beuren syndrome AF073519 SERF1A small EDRK-rich Alternativesplicing 193 4161 factor 1A (telomeric) AF073931 CACNA1H calciumchannel, Ionic channel, Transmembrane, Ion 194 4162 voltage-dependent,transport, Voltage-gated channel, alpha 1H subunit Calcium channel,Glycoprotein, Repeat, Multigene family, Calcium- binding,Phosphorylation, Alternative splicing AF077965 CLN3ceroid-lipofuscinosis, Transmembrane, Lysosome, 195 4163 neuronal 3,juvenile Glycoprotein, Alternative splicing, (Batten, Spielmeyer-Neuronal ceroid lipofuscinosis, Vogt disease) Disease mutation AF078843LOC51202 DEAD (Asp-Glu-Ala- ATP-binding, Helicase, Hydrolase, 196 4164Asp) box polypeptide Hypothetical protein 47 AF085243 ZNF236 zinc fingerprotein Metal-binding, Nuclear protein, Zinc, 197 4165 236 Zinc-finger,Hypothetical protein, Transcription regulation, DNA- binding, Repeat,Alternative splicing AF090935 C20orf3 Homo sapiens clone Transmembrane,Signal-anchor, 198 4166 HQ0569. Glycoprotein, Polymorphism AF097021GW112 differentially 199 4167 expressed in hematopoietic lineagesAF112213 C20orf24 chromosome 20 Alternative splicing 200 4168 openreading frame 24 AF112219 ESD esterase Hydrolase, Serine esterase, 2014169 D/formylglutathione Polymorphism hydrolase AF113694 NF2neurofibromin 2 Structural protein, Cytoskeleton, 202 4170 (bilateralacoustic Anti-oncogene, Disease mutation, neuroma) Alternative splicing,Deafness, 3D- structure AF114264 nexilin nexilin (F actin Hypotheticalprotein 203 4171 binding protein) AF116238 PUS1 pseudouridylate Lyase,tRNA processing, Nuclear 204 4172 synthase 1 protein AF117236 MATR3matrin 3 Nuclear protein, RNA-binding, 205 4173 Repeat, Zinc-fingerAF119665 PP pyrophosphatase Hydrolase, Metal-binding, 206 4174(inorganic) Magnesium AF119856 PRO1851 Homo sapiens Acute phase, Serineprotease 207 4175 mRNA for PK-120, inhibitor, Repeat, Signal, Multigenecomplete cds. family, Glycoprotein, Alternative splicing, PolymorphismAF121856 SNX6 sorting nexin 6 Hypothetical protein, Transport, 208 4176Protein transport AF126749 SCA8 SCA8 mRNA, repeat 209 4177 regionAF127765 CAPN3 calpain 3, (p94) Hydrolase, Thiol protease, Calcium- 2104178 binding, Multigene family, Repeat, Disease mutation, Polymorphism,Alternative splicing AF131760 LRP10 low density Hypothetical protein,Plasmid 211 4179 lipoprotein receptor- related protein 10 AF131764 MPP5membrane protein, Hypothetical protein, SH3 domain, 212 4180palmitoylated 5 Membrane (MAGUK p55 subfamily member 5) AF131768FLJ13657 chromosome 9 open Hypothetical protein 213 4181 reading frame82 AF131774 FLJ14800 hypothetical protein Hypothetical protein 214 4182FLJ14800 AF131775 MGC5560 hypothetical protein Hypothetical protein 2154183 MGC5560 AF131784 RAB27B, member GTP-binding, Lipoprotein, 216 4184RAS oncogene Prenylation family AF131803 MGC5508 hypothetical proteinHypothetical protein 217 4185 MGC5508 AF131812 likely ortholog ofHypothetical protein 218 4186 mouse monocyte macrophage 19 AF131838FLJ12806 hypothetical protein Hypothetical protein 219 4187 FLJ12806AF131842 KIAA1857 netrin G2 Hypothetical protein, EGF-like 220 4188domain, Laminin EGF-like domain, Neurogenesis, Glycoprotein, GPI-anchor, Membrane, Signal, Repeat, Lipoprotein AF131859 PA sulfidequinone Oxidoreductase, Flavoprotein, FAD, 221 4189 reductase-like NADP,Mitochondrion, Transit (yeast) peptide, Polymorphism AF134404 FADS3fatty acid desaturase 3 Heme 222 4190 AF146277 CD2AP CD2-associated SH3domain, SH3-binding, 223 4191 protein Phosphorylation, Coiled coil,Repeat AF152338 PCDHGC4 protocadherin Calcium, Calcium-binding, Cell 2244192 gamma subfamily C, 3 adhesion, Glycoprotein, Transmembrane,Alternative splicing, Repeat, Signal, Multigene family AF152339 PCDHGC5protocadherin Calcium, Calcium-binding, Cell 225 4193 gamma subfamily C,3 adhesion, Glycoprotein, Transmembrane, Alternative splicing, Repeat,Signal, Multigene family AF155107 FLJ11806 nuclear protein Plasmid,Hypothetical protein 226 4194 UKp68 AF156603 WBSCR14 Williams BeurenTranscription regulation, Repressor, 227 4195 syndrome Nuclear protein,DNA-binding, chromosome region Williams-Beuren syndrome, 14 Alternativesplicing AF161339 ARHGAP9 Rho GTPase Hypothetical protein, SH3 domain228 4196 activating protein 9 AF161417 DKFZp564D177 nipsnap homolog 3AHypothetical protein 229 4197 (C. elegans) AF161442 HSPC324 Similar toHSPC324 230 4198 (LOC389811), mRNA AF167706 CRIM1 cysteine-rich motorSignal 231 4199 neuron 1 AF187859 HSPBP1 hsp70-interacting Hypotheticalprotein 232 4200 protein AF202063 FGFR4 fibroblast growth ATP-binding,Immunoglobulin 233 4201 factor receptor 4 domain, Kinase, Receptor,Transferase, Tyrosine-protein kinase, Glycoprotein, Phosphorylation,Transmembrane, Repeat, Signal, Polymorphism, 3D- structure AF209931 7h3hypothetical protein Hypothetical protein 234 4202 FLJ13511 AF212842LILRA3 leukocyte Ig-like Receptor, Repeat, Signal, Immune 235 4203receptor 9 response, Immunoglobulin domain, Glycoprotein, Antigen,Multigene family, Polymorphism AF217798 NDEL1 nudE nuclear Hypotheticalprotein 236 4204 distribution gene E homolog like 1 (A. nidulans)AF220417 LGTN ligatin Membrane, Alternative splicing 237 4205 AF222694LGALS12 lectin, galactoside- Galectin, Lectin, Repeat, Nuclear 238 4206binding, soluble, 12 protein, Alternative splicing (galectin 12)AF227924 SIGLEC9 sialic acid binding Ig- Cell adhesion, Lectin, Antigen,239 4207 like lectin 9 Transmembrane, Signal, Glycoprotein,Immunoglobulin domain, Repeat, Polymorphism AF228704 GSR glutathioneFAD, Flavoprotein, Oxidoreductase, 240 4208 reductase Redox-activecenter, NADP, Acetylation, Alternative initiation, Mitochondrion,Transit peptide, 3D- structure, Polymorphism AF232216 PIH1 Homo sapiens241 4209 pregnancy-induced hypertension syndrome-related protein (PIH1)mRNA, partial cds. AF237413 RAP1GDS1 RAP1, GTP-GDP GTPase activation,Repeat, 242 4210 dissociation Alternative splicing stimulator 1 AF241831HABP4 hyaluronan binding Hypothetical protein 243 4211 protein 4AF242771 Mesenchymal stem 244 4212 cell protein DSC96 mRNA, partial cdsAF244088 ZNF16 zinc finger protein 16 Hypothetical protein,Metal-binding, 245 4213 (KOX 9) Nuclear protein, Zinc, Zinc-finger,Transcription regulation, DNA- binding, Repeat AF246221 ITM2B integralmembrane Hypothetical protein, 246 4214 protein 2B Transmembrane,Signal-anchor, Disease mutation, Amyloid, Deafness AF257175 PECIperoxisomal D3,D2- Isomerase, Peroxisome, 247 4215 enoyl-CoAHypothetical protein isomerase AF260261 ABI-2 abl interactor 2 Kinase,SH3 domain 248 4216 AF272357 NPDC1 neural proliferation, Signal,Transmembrane, 249 4217 differentiation and Hypothetical proteincontrol, 1 AI076473_RC rap2 interacting Hypothetical protein 250 4218protein x AI282511_RC PTRF hypothetical protein Hypothetical protein 2514219 FLJ10534 AI286310_RC HSPA5 qu91g07.x1 ATP-binding, Endoplasmicreticulum, 252 4220 NCI_CGAP_Gas4 Signal Homo sapiens cDNA clone IMAGE:1979484 3′ similar to gb: M19645_cds1 78 KD GLUCOSE REGULATED PROTEINPRECURSOR (HUMAN); mRNA sequence. AI339981_RC hypothetical protein 2534221 LOC153346 AI347139_RC hypothetical protein 254 4222 MGC39372AI355990_RC qy51g12.x1 255 4223 NCI_CGAP_Brn23 Homo sapiens cDNA cloneIMAGE: 2015590 3′, mRNA sequence. AI434777_RC CDNA FLJ44280 fis, 2564224 clone TRACH2001684 AI493593_RC th39c02.x1 257 4225 NCI_CGAP_Pan1Homo sapiens cDNA clone IMAGE: 2120642 3′, mRNA sequence. AI668686_RCFLJ38281 hypothetical protein Hypothetical protein, Metal-binding, 2584226 FLJ38281 Zinc, Zinc-finger AI677876_RC CDNA clone 259 4227 IMAGE:4648334, partial cds AI695056_RC Sarcoma antigen 260 4228 NY-SAR-79mRNA, partial cds AI928427_RC Transcribed 261 4229 sequences AJ000480C8FW phosphoprotein ATP-binding, Receptor, Transferase 262 4230regulated by mitogenic pathways AJ010228 RFPL1 ret finger protein-like 1Zinc-finger, Metal-binding 263 4231 AJ010842 NTPBP XPA binding protein 1GTP-binding 264 4232 AJ011414 plexin- plexin B1 Hypothetical protein,Receptor, 265 4233 B1/SEP Signal AJ133115 THG-1 TSC-22-like Hypotheticalprotein, Transcription 266 4234 regulation, Repressor, Nuclear proteinAJ225028 GABBR1 gamma-aminobutyric Hypothetical protein, G-protein 2674235 acid (GABA) B coupled receptor, Postsynaptic receptor, 1 membrane,Repeat, Signal, Transmembrane, Coiled coil, Sushi, Glycoprotein,Alternative splicing, Polymorphism, Receptor AJ243107 APAF1 Homo sapiensApoptosis, ATP-binding, Repeat, 268 4236 mRNA for apoptotic WD repeat,Alternative splicing, 3D- protease activating structure factor-1 (Apaf-1gene) (short form). AJ249377 IGHM immunoglobulin Immunoglobulin domain,269 4237 lambda joining 3 Immunoglobulin C region, Glycoprotein, Repeat,Pyrrolidone carboxylic acid, Polymorphism, Membrane, Hypotheticalprotein, Receptor, T-cell, Signal AJ270996 TRPM5 transient receptorIonic channel, Transmembrane 270 4238 potential cation channel,subfamily M, member 5 AJ271684 CLECSF5 C-type (calcium Transmembrane,Lectin 271 4239 dependent, carbohydrate- recognition domain) lectin,superfamily member 5 AJ272057 STRAIT11499 MID1 interacting Hypotheticalprotein 272 4240 G12-like protein AK000001 FLJ00001 chromosome 9 openHypothetical protein 273 4241 reading frame 28 AK000004 FGD3 FGD1family, 274 4242 member 3 AK000007 FLJ00007 hypothetical protein SH3domain 275 4243 FLJ00007 AK000014 HYPE Huntingtin Hypothetical protein276 4244 interacting protein E AK000035 FLJ22390 hypothetical proteinHypothetical protein 277 4245 FLJ22390 AK000168 KIAA1919 Homo sapienscDNA Hypothetical protein 278 4246 FLJ20161 fis, clone COL09252, highlysimilar to L33930 Homo sapiens CD24 signal transducer mRNA. AK000175hypothetical protein 279 4247 LOC93444 AK000212 FLJ10140 tRNA (5-Hypothetical protein, Transferase, 280 4248 methylaminomethyl-Methyltransferase, tRNA processing 2-thiouridylate)- methyltransferase 1AK000216 FLJ20209 hypothetical protein 281 4249 FLJ20209 AK000242 RALGDSral guanine Guanine-nucleotide releasing factor, 282 4250 nucleotide3D-structure, Hypothetical protein dissociation stimulator AK000260CDK5RAP3 Homo sapiens cDNA 283 4251 FLJ20253 fis, clone COLF6895.AK000354 KIAA1892 KIAA1892 Hypothetical protein, Repeat, WD 284 4252repeat AK000425 FLJ25555 hypothetical protein Hypothetical protein 2854253 FLJ25555 AK000435 LOC90987 zinc finger protein Hypotheticalprotein, Metal-binding, 286 4254 251 Nuclear protein, Zinc, Zinc-fingerAK000539 DKFZP564K0822 hypothetical protein Hypothetical protein 2874255 DKFZp564K0822 AK000552 WDR5 WD repeat domain 5 Hypotheticalprotein, WD repeat, 288 4256 Repeat AK000617 NFRKB hypothetical proteinHypothetical protein, Ligase, Ubl 289 4257 LOC92912 conjugation pathwayAK000660 cyclin-dependent 290 4258 kinase 6 AK000684 FLJ22104hypothetical protein Hypothetical protein 291 4259 FLJ22104 AK000689CLONE24945 arrestin domain Hypothetical protein 292 4260 containing 2AK000703 FLJ20696 hypothetical protein Hypothetical protein 293 4261FLJ20696 AK000729 solute carrier family Hypothetical protein 294 4262 36(proton/amino acid symporter), member 1 AK000757 BCL2L1 sortilin 1Apoptosis, Mitochondrion, 295 4263 Alternative splicing, Transmembrane,3D-structure AK000787 CDNA FLJ20780 fis, 296 4264 clone COL04256AK000803 hypothetical protein 297 4265 LOC90624 AK000808 MGC4796Ser/Thr-like kinase Hypothetical protein, ATP-binding, 298 4266 Kinase,Serine/threonine-protein kinase, Transferase AK000822 DKFZP564M182DKFZP564M182 Hypothetical protein 299 4267 protein AK000824 TCTA T-cellleukemia 300 4268 translocation altered gene AK000838 KIAA1295 KIAA1295protein Hypothetical protein 301 4269 AK000933 opsin 3 Photoreceptor,Retinal protein, 302 4270 (encephalopsin, Transmembrane, Lipoprotein,panopsin) Palmitate, G-protein coupled receptor, GTPase activationAK000939 hypothetical protein 303 4271 LOC286272 AK000967 3PAPphosphatidylinositol- Hypothetical protein 304 4272 3-phosphateassociated protein AK001022 ISL2 ISL2 transcription Homeobox,DNA-binding, 305 4273 factor, Developmental protein, NuclearLIM/homeodomain, protein, Repeat, LIM domain, Metal- (islet-2) binding,Zinc, Multigene family AK001036 MAD, mothers Transcription regulation,Multigene 306 4274 against family, Phosphorylation decapentaplegichomolog 5 (Drosophila) AK001069 UPF3A CDNA FLJ10207 fis, 307 4275 cloneHEMBA1005475 AK001163 PAICS phosphoribosylaminoimidazole Multifunctionalenzyme, Purine 308 4276 carboxylase, biosynthesis, Ligase, Lyase,phosphoribosylaminoimidazole Decarboxylase succinocarboxamide synthetaseAK001166 FLJ11252 HBxAg Hypothetical protein 309 4277 transactivatedprotein 1 AK001228 chromosome 6 open 310 4278 reading frame 107 AK001319C8FW phosphoprotein ATP-binding, Receptor, Transferase 311 4279regulated by mitogenic pathways AK001362 ESDN endothelial andHypothetical protein 312 4280 smooth muscle cell- derived neuropilin-like protein AK001394 hypothetical protein 313 4281 DKFZp762K222AK001452 FLJ10839 Homo sapiens cDNA Hypothetical protein 314 4282FLJ10590 fis, clone NT2RP2004392, weakly similar to MNN4 PROTEIN.AK001469 GNPNAT1 glucosamine- Hypothetical protein, Transferase 315 4283phosphate N- acetyltransferase 1 AK001478 ARHU ras homolog geneGTP-binding, Lipoprotein, 316 4284 family, member U Prenylation AK001492FLJ10637 hypothetical protein Hypothetical protein 317 4285 FLJ10637AK001499 FLJ10637 hypothetical protein Hypothetical protein 318 4286FLJ10637 AK001503 CDNA FLJ10641 fis, Metal-binding, Zinc, Zinc-finger319 4287 clone NT2RP2005748 AK001526 DKFZp667B1218 hypothetical proteinHypothetical protein 320 4288 DKFZp667B1218 AK001536 Human full-lengthPlasmid 321 4289 cDNA 5-PRIME end of clone CS0DK007YB08 of HeLa cells ofHomo sapiens (human) AK001539 TEM6 tensin-like SH2 Hypothetical protein322 4290 domain containing 1 AK001565 AP3M1 adaptor-related Golgi stack,Protein transport, 323 4291 protein complex 3, Transport, Hypotheticalprotein mu 1 subunit AK001579 ARAP3 ARF-GAP, RHO- Hypothetical protein324 4292 GAP, ankyrin repeat and plekstrin homology domains- containingprotein 3 AK001612 hypothetical protein 325 4293 LOC90784 AK001630 ETS1v-ets Proto-oncogene, Nuclear protein, 326 4294 erythroblastosisTranscription regulation, DNA- virus E26 oncogene binding,Phosphorylation, Alternative homolog 1 (avian) splicing, 3D-structureAK001731 MGC17943 hypothetical protein Hypothetical protein 327 4295MGC17943 AK001758 THOC2 THO complex 2 Transport, mRNA transport, mRNA328 4296 processing, mRNA splicing, Nuclear protein, RNA-binding,Alternative splicing AK001822 chromosome 9 open Hypothetical protein 3294297 reading frame 37 AK001913 CL25084 XTP3-transactivated Hypotheticalprotein 330 4298 protein B AK001980 ADPRTL2 ADP- Transferase,Glycosyltransferase, 331 4299 ribosyltransferase NAD, DNA-binding,Nuclear protein, (NAD+; poly(ADP- Alternative splicing ribose)polymerase)- like 2 AK002039 MRVI1 murine retrovirus 332 4300integration site 1 homolog AK002081 FLJ10287 hypothetical proteinHypothetical protein 333 4301 FLJ10287 AK002141 PIK4CA Homo sapiens cDNATransferase, Kinase 334 4302 FLJ11279 fis, clone PLACE1009444, highlysimilar to PHOSPHATIDYLINOSITOL 4-KINASE ALPHA (EC 2.7.1.67). AK002146hypothetical protein 335 4303 LOC153684 AK002174 KLHL5 kelch-like 5Cytoskeleton, Actin-binding, Repeat, 336 4304 (Drosophila) Kelch repeat,Alternative splicing AL049232 Homo sapiens 337 4305 mRNA; cDNADKFZp564P1816 (from clone DKFZp564P1816). AL049266 Homo sapiens 338 4306mRNA; cDNA DKFZp564F093 (from clone DKFZp564F093). AL049279 MRNA; cDNA339 4307 DKFZp564I083 (from clone DKFZp564I083) AL049299 DJ465N24.2.1hypothetical protein Hypothetical protein 340 4308 dJ465N24.2.1 AL049309SFRS12 splicing factor, Nuclear protein, mRNA processing, 341 4309arginine/serine-rich mRNA splicing, Spliceosome, 12 Alternative splicingAL049365 FTL hypothetical protein Acetylation, Iron storage, Multigene342 4310 MGC50853 family AL049381 pre-B-cell leukemia Transcriptionregulation, DNA- 343 4311 transcription factor 1 binding, Nuclearprotein, Activator, Repressor, Homeobox, Proto- oncogene, Chromosomaltranslocation, Alternative splicing, Steroidogenesis, Sexualdifferentiation, 3D-structure AL049397 CGI-146 protein Hypotheticalprotein 344 4312 AL049415 ADAM19 a disintegrin and Hydrolase,Metalloprotease, Zinc, 345 4313 metalloproteinase Signal, Glycoprotein,Zymogen, domain 19 (meltrin Transmembrane, EGF-like domain, beta)SH3-binding, Alternative splicing, Hypothetical protein AL049431FLJ20619 hypothetical protein Hypothetical protein 346 4314 FLJ20619AL049450 hypothetical protein 347 4315 LOC339287 AL049471 AT richinteractive Hypothetical protein 348 4316 domain 5B (MRF1- like)AL049962 hypothetical protein 349 4317 LOC286148 AL049963 LOC64116solute carrier family Hypothetical protein 350 4318 39 (zinctransporter), member 8 AL050002 hypothetical protein Hypotheticalprotein 351 4319 LOC169611 AL050021 solute carrier family Hypotheticalprotein, 352 4320 7 (cationic amino Transmembrane, Glycoprotein, acidtransporter, y+ Transport, Amino-acid transport, system), member 1Receptor AL050022 DKFZP564D116 DKFZP564D116 Hypothetical protein 3534321 protein AL050050 TULIP1 GTPase activating Hypothetical protein 3544322 RANGAP domain- like 2 pseudogene AL050060 DKFZP566H073 DKFZP566H073Hypothetical protein, Metal-binding, 355 4323 protein Zinc, Zinc-fingerAL050091 GRINL1A glutamate receptor, Hypothetical protein, Receptor 3564324 ionotropic, N-methyl D-aspartate-like 1A AL050126 LAP1Blamina-associated Hypothetical protein 357 4325 polypeptide 1B AL050148sorting nexin 1 Transport, Protein transport, Golgi 358 4326 stack,Alternative splicing AL050163 PIK3AP hematopoietic cell Hypotheticalprotein, 359 4327 signal transducer Transmembrane AL050164 CDYLchromodomain Hypothetical protein, Nuclear protein 360 4328 protein,Y-like AL050170 SLC26A6 solute carrier family Hypothetical protein, 3614329 26, member 6 Transmembrane, Alternative splicing, PolymorphismAL050173 C21orf25 chromosome 21 Hypothetical protein 362 4330 openreading frame 25 AL050217 BRD2 dehydrogenase/reductase Oxidoreductase363 4331 (SDR family) member 1 AL050346 C22orf3 chromosome 22Hypothetical protein 364 4332 open reading frame 3 AL079294 MRNA fulllength Hypothetical protein 365 4333 insert cDNA clone EUROIMAGE 362780AL079298 MCCC2 methylcrotonoyl- Mitochondrion, Transit peptide, 366 4334Coenzyme A Ligase, Disease mutation, carboxylase 2 (beta) Alternativesplicing AL080110 progestin and Hypothetical protein 367 4335 adipoQreceptor family member III AL080114 chromosome 10 Hypothetical protein368 4336 open reading frame 72 AL080125 ZNF20 zinc finger protein 20Hypothetical protein, Metal-binding, 369 4337 (KOX 13) Nuclear protein,Zinc, Zinc-finger, Transcription regulation, DNA- binding, RepeatAL080156 DKFZP434J214 TCDD-inducible Hypothetical protein 370 4338poly(ADP-ribose) polymerase AL080169 DKFZP434C171 DKFZP434C171Hypothetical protein 371 4339 protein AL080182 N-deacetylase/N-Hypothetical protein, Transferase, 372 4340 sulfotransferaseTransmembrane, Glycoprotein, Golgi (heparan stack, Signal-anchorglucosaminyl) 2 AL080192 hypothetical protein Hypothetical protein 3734341 LOC253782 AL096745 TBCD tubulin-specific Hypothetical protein 3744342 chaperone d AL109669 IL16 interleukin 16 Cytokine, Chemotaxis,Repeat, 3D- 375 4343 (lymphocyte structure chemoattractant factor)AL109693 FLJ12587 hypothetical protein Hypothetical protein 376 4344FLJ12587 AL109695 solute carrier organic Transmembrane, Transport, Ion377 4345 anion transporter transport, Glycoprotein family, member 3A1AL109699 MRNA full length Hypothetical protein 378 4346 insert cDNAclone EUROIMAGE 375854 AL109705 MRNA full length 379 4347 insert cDNAclone EUROIMAGE 73337 AL109786 WDR9 chromosome 21 Bromodomain, Repeat,WD repeat 380 4348 open reading frame 107 AL109817 FTCDformiminotransferase Hypothetical protein, Transferase, 381 4349cyclodeaminase Lyase, Histidine metabolism, Multifunctional enzyme,Pyridoxal phosphate, Folate-binding, Alternative splicing, Diseasemutation, Polymorphism AL110152 CD109 antigen (Gov Hypothetical protein382 4350 platelet alloantigens) AL110188 ZNF10 zinc finger protein 10Hypothetical protein, Metal-binding, 383 4351 (KOX 1) Nuclear protein,Zinc, Zinc-finger, Transcription regulation, DNA- binding, RepeatAL110200 Homo sapiens 384 4352 mRNA; cDNA DKFZp586B0922 (from cloneDKFZp586B0922). AL110202 PORIMIN pro-oncosis receptor Hypotheticalprotein, Receptor, 385 4353 inducing membrane Transmembrane injury geneAL110210 PTPN23 protein tyrosine Hydrolase, Hypothetical protein, 3864354 phosphatase, non- Receptor receptor type 23 AL110218 SLB selectiveLIM binding Hypothetical protein 387 4355 factor, rat homolog AL110238RRN3 RNA polymerase I Initiation factor, Hypothetical protein 388 4356transcription factor RRN3 AL110262 NCBP2 nuclear cap binding Transport,mRNA transport, Nuclear 389 4357 protein subunit 2, protein,RNA-binding, 3D-structure 20 kDa AL110277 KIAA0916 protein associatedHypothetical protein 390 4358 with Myc AL117415 ADAM33 Homo sapiensHypothetical protein, Hydrolase, 391 4359 mRNA; cDNA Metalloprotease,Zinc, Signal, DKFZp434K0521 Glycoprotein, Zymogen, (from cloneTransmembrane, EGF-like domain, DKFZp434K0521). Alternative splicing,Integrin, Protease AL117435 DKFZP434I216 DKFZP434I216 Hypotheticalprotein 392 4360 protein AL117448 RAB6IP1 RAB6 interacting Hypotheticalprotein 393 4361 protein 1 AL117452 FTHFSDC1 formyltetrahydrofolateHypothetical protein 394 4362 synthetase domain containing 1 AL117457CFL2 cofilin 2 (muscle) Nuclear protein, Actin-binding, 395 4363Cytoskeleton, Phosphorylation, Alternative splicing AL117458 IHPK2inositol Hypothetical protein, Kinase 396 4364 hexaphosphate kinase 2AL117462 ZFP385 zinc finger protein Metal-binding, Zinc, Zinc-finger,397 4365 385 Hypothetical protein AL117478 AGS3 G-protein signallingHypothetical protein 398 4366 modulator 1 (AGS3- like, C. elegans)AL117519 hypothetical protein Hypothetical protein, Metal-binding, 3994367 LOC152485 Zinc, Zinc-finger AL117573 DKFZP434F2021 DKFZP434F2021Hypothetical protein 400 4368 protein AL117578 DKFZP434C128 chromosome21 Hypothetical protein 401 4369 open reading frame 30 AL117609DKFZp564O0463 DKFZP564O0463 Hypothetical protein, Repeat, WD 402 4370protein repeat AL117639 FLJ12890 CCR4-NOT Hypothetical protein 403 4371transcription complex, subunit 10 AL117643 activin A receptor, Receptor,Transferase, 404 4372 type IB Serine/threonine-protein kinase,ATP-binding, Transmembrane, Glycoprotein, Signal, Alternative splicing,Phosphorylation, Polymorphism AL117645 EG1 endothelial-derivedHypothetical protein 405 4373 gene 1 AL117654 ARH LDL receptorHypothetical protein 406 4374 adaptor protein AL122053 TRIM3 tripartitemotif- Zinc-finger, Coiled coil, Alternative 407 4375 containing 3splicing AL122091 LOC56965 hypothetical protein Hypothetical protein 4084376 from EUROIMAGE 1977056 AL122097 FLJ12519 hypothetical proteinHypothetical protein, Repeat, WD 409 4377 FLJ12519 repeat AL122098 NICALNEDD9 interacting Hypothetical protein, LIM domain, 410 4378 proteinwith calponin Metal-binding, Zinc, Cytoskeleton homology and LIM domainsAL122123 MRNA; cDNA 411 4379 DKFZp434M038 (from clone DKFZp434M038)AL133021 STAB2 stabilin 2 EGF-like domain, Laminin EGF-like 412 4380domain, Hypothetical protein, Receptor AL133071 DKFZp434I1117hypothetical protein Hypothetical protein 413 4381 DKFZp434I1117AL133092 DKFZp434I0428 dispatched homolog Hypothetical protein 414 43821 (Drosophila) AL133094 PHF10 PHD finger protein Hypothetical protein415 4383 10 AL133115 cytosolic ovarian Biological rhythms, Electron 4164384 carcinoma antigen 1 transport, Growth regulation, Oxidoreductase,NAD, Membrane, Copper, Glycoprotein AL133116 FKBP10 Homo sapiensIsomerase, Rotamase, Endoplasmic 417 4385 mRNA; cDNA reticulum,Calcium-binding, DKFZp586I0821 Glycoprotein, Phosphorylation, (fromclone Repeat, Signal, Hypothetical protein DKFZp586I0821). AL133117 THOcomplex 2 Transport, mRNA transport, mRNA 418 4386 processing, mRNAsplicing, Nuclear protein, RNA-binding, Alternative splicing AL133426AKAP13 A kinase (PRKA) Kinase, Receptor, cAMP, 419 4387 anchor protein13 Hypothetical protein AL133572 DKFZp434I0535 Homo sapiens Hypotheticalprotein 420 4388 mRNA; cDNA DKFZp434I0535 (from clone DKFZp434I0535);partial cds. AL133577 MRNA; cDNA 421 4389 DKFZp434G0972 (from cloneDKFZp434G0972) AL133580 SCOC short coiled-coil Hypothetical protein 4224390 protein AL133581 FLJ25785 solute carrier family Hypotheticalprotein 423 4391 39 (zinc transporter), member 13 AL133592 MGC15548 zincfinger protein Hypothetical protein, Metal-binding, 424 4392 496 Zinc,Zinc-finger AL133622 KIAA0876 jumonji domain Hypothetical protein 4254393 containing 2B AL133632 DKFZp434E1818 Similar to Hypotheticalprotein, Metal-binding, 426 4394 hypothetical protein Zinc, Zinc-finger(LOC389822), mRNA AL133645 hypothetical protein 427 4395 LOC90133AL133662 KIAA0913 KIAA0913 protein Hypothetical protein 428 4396AL136549 CYFIP2 cytoplasmic FMR1 Hypothetical protein 429 4397interacting protein 2 AL137273 DKFZP434I0714 hypothetical proteinHypothetical protein 430 4398 DKFZP434I0714 AL137298 DNAJB6 MRNA; cDNAChaperone, Alternative splicing 431 4399 DKFZp434N2116 (from cloneDKFZp434N2116) AL137302 TEX27 testis expressed Hypothetical protein 4324400 sequence 27 AL137397 FLJ21820 hypothetical protein Hypotheticalprotein 433 4401 FLJ21820 AL137421 RBM10 RNA binding motif Hypotheticalprotein, Metal-binding, 434 4402 protein 10 Zinc, Zinc-finger,RNA-binding, Nuclear protein, Repeat AL137423 GU2 DEAD (Asp-Glu-Ala-ATP-binding, Helicase, Hydrolase, 435 4403 Asp) box polypeptideHypothetical protein 50 AL137431 WBSCR17 Williams-Beuren Transferase,Hypothetical protein 436 4404 syndrome chromosome region 17 AL137442C20orf177 chromosome 20 Hypothetical protein 437 4405 open reading frame177 AL137473 C20orf67 Homo sapiens Alternative splicing, Hypothetical438 4406 mRNA; cDNA protein DKFZp434E1723 (from clone DKFZp434E1723);partial cds. AL137477 CDH24 cadherin-like 24 Hypothetical protein,Calcium, 439 4407 Calcium-binding, Cell adhesion, Glycoprotein,Transmembrane, Repeat, Signal, Multigene family, Alternative splicing,Plasmid AL137480 FNBP4 formin binding Hypothetical protein 440 4408protein 4 AL137491 hypothetical protein 441 4409 LOC148696 AL137509DKFZp761A052 hypothetical protein Hypothetical protein 442 4410DKFZp761A052 AL137514 IHPK2 inositol Hypothetical protein, Kinase 4434411 hexaphosphate kinase 2 AL137516 FLJ22059 zinc finger proteinHypothetical protein, Metal-binding, 444 4412 574 Zinc, Zinc-finger,Nuclear protein AL137557 KIAA1529 KIAA1529 Hypothetical protein 445 4413AL137567 KIAA1238 KIAA1238 protein Hypothetical protein 446 4414AL137579 SNX26 sorting nexin 26 Hypothetical protein, Transport, 4474415 Protein transport AL137597 C20orf110 chromosome 20 448 4416 openreading frame 110 AL137615 MKNK2 MAP kinase- Hypothetical protein,ATP-binding, 449 4417 interacting Kinase, Serine/threonine-proteinserine/threonine kinase, Transferase, Translation kinase 2 regulation,Phosphorylation, Alternative splicing AL137631 FBXW5 Homo sapiensHypothetical protein, Repeat, WD 450 4418 mRNA; cDNA repeat DKFZp434B205(from clone DKFZp434B205); partial cds. AL137639 KIAA0721 TSPY-like 4Hypothetical protein 451 4419 AL137648 DKFZP434J1813 ER-resident proteinRedox-active center, Hypothetical 452 4420 ERdj5 protein AL137655 Homosapiens Hypothetical protein 453 4421 mRNA; cDNA DKFZp434B2016 (fromclone DKFZp434B2016). AL137662 DKFZp434P086 hypothetical proteinHypothetical protein, ATP-binding, 454 4422 LOC340371 TransferaseAL137663 FLJ21791 pleckstrin homology- Hypothetical protein 455 4423like domain, family B, member 2 AL137665 TUBGCP6 tubulin, gammaMicrotubule, Repeat, Alternative 456 4424 complex associated splicingprotein 6 AL137667 MAPK8 Homo sapiens Transferase, Serine/threonine- 4574425 mRNA; cDNA protein kinase, ATP-binding, DKFZp434B231Phosphorylation, Alternative splicing (from clone DKFZp434B231).AL137707 LOC55901 TPTE and PTEN Signal 458 4426 homologous inositollipid phosphatase pseudogene AL137727 C14orf9 chromosome 14 Hypotheticalprotein, 459 4427 open reading frame 9 Transmembrane, Alternativesplicing AL137733 hypothetical protein Hypothetical protein 460 4428LOC284701 AL137736 Rho guanine Hypothetical protein 461 4429 nucleotideexchange factor (GEF) 19 AL137764 LOC64744 hypothetical proteinHypothetical protein 462 4430 AL133206 AL157432 TERA chromosome 12Hypothetical protein 463 4431 open reading frame 14 AL157449 LOC84687protein phosphatase Hypothetical protein 464 4432 1, regulatory subunit9B, spinophilin AL157454 FLJ21313 HCV NS3- Hypothetical protein 465 4433transactivated protein 2 AL157455 Clone 466 4434 IMAGE: 5288750, mRNAAL157457 PP1628 PH domain- Hypothetical protein 467 4435 containingprotein AL157465 FLJ20186 hypothetical protein Hypothetical protein 4684436 FLJ20186 AL157480 SH3BP1 lectin, galactoside- GTPase activation,SH3-binding, 469 4437 binding, soluble, 1 Hypothetical protein,Galectin, (galectin 1) Lectin, Multigene family, Acetylation AL157484MRNA; cDNA 470 4438 DKFZp762M127 (from clone DKFZp762M127) AL161960FLJ21324 chromosome 21 Hypothetical protein 471 4439 open reading frame97 AL161972 ICAM2 hypothetical protein 3D-structure, Cell 472 4440FLJ11724 adhesion, Glycoprotein, Immunoglobulin domain, Repeat, Signal,Transmembrane AL161977 PCTK3 PCTAIRE protein Hypothetical protein,ATP-binding, 473 4441 kinase 3 Kinase, Serine/threonine-protein kinase,Transferase AL161983 hypothetical protein 474 4442 MGC39820 AL161994HEI10 cyclin B1 interacting Ubl conjugation pathway, Ligase, 475 4443protein 1 Nuclear protein, Metal-binding, Zinc, Coiled coil,Zinc-finger, Phosphorylation, Ubl conjugation AL162013 PLXNA1 Homosapiens Hypothetical protein 476 4444 mRNA; cDNA DKFZp761P19121 (fromclone DKFZp761P19121); partial cds. AL162039 MOB1, Mps One 477 4445Binder kinase activator-like 1A (yeast) AL162062 LOC91010 formin-like 3Hypothetical protein 478 4446 AL353934 MUS81 MUS81 Endonuclease,Hypothetical protein 479 4447 endonuclease homolog (yeast) AL353952PI4KII phosphatidylinositol Hypothetical protein, Kinase 480 44484-kinase type II AL353953 FLJ13055 lipid phosphate Hypothetical protein481 4449 phosphatase-related protein type 2 AL355708 NEO1 neogeninhomolog 1 Cell adhesion, Repeat, Signal, 482 4450 (chicken)Transmembrane, Immunoglobulin domain, Glycoprotein, Alternative splicingAW190932_RC GPI xl66g09.x1 Gluconeogenesis, Glycolysis, 483 4451NCI_CGAP_Pan1 Isomerase, Growth factor, Cytokine, Homo sapiens cDNADisease mutation, 3D-structure, clone Hypothetical protein IMAGE:2679712 3′, mRNA sequence. AW273216_RC ring finger protein Hypotheticalprotein, Metal-binding, 484 4452 149 Zinc, Zinc-finger AW419203_RCKIAA0601 amine oxidase Hypothetical protein 485 4453 (flavin containing)domain 2 AW673036_RC PPP1R3B hypothetical protein Hypothetical protein486 4454 LOC286044 BE671663_RC EVIN2 epidermodysplasia Transmembrane,Hypothetical 487 4455 verruciformis 2 protein BE672528_RCcyclin-dependent 488 4456 kinase 6 Contig10037_RC hypothetical proteinHypothetical protein 489 4457 DKFZp667C165 Contig1007_RC LOC51754hypothetical protein Hypothetical protein 490 4458 LOC283070Contig10162_RC MGC14276 hypothetical protein Hypothetical protein 4914459 MGC14276 Contig1030_RC FLJ00026 dedicator of Guanine-nucleotidereleasing factor 492 4460 cytokinesis 8 Contig10363_RC MRF2 AT richinteractive Hypothetical protein 493 4461 domain 5B (MRF1- like)Contig10373_RC hypothetical protein Hypothetical protein 494 4462MGC21854 Contig10418_RC Transcribed 495 4463 sequences Contig10429_RCDKFZp434H2111 hypothetical protein Hypothetical protein 496 4464DKFZp434H2111 Contig10531_RC microtubule- Microtubule, Cytoskeleton,Repeat, 497 4465 associated protein Alternative splicing, Acetylation,tau Phosphorylation, Glycoprotein, Polymorphism, Disease mutation,Alzheimer's disease, 3D-structure, Hypothetical protein Contig1056_RCLOC57106 K562 cell-derived Hypothetical protein 498 4466leucine-zipper-like protein 1 Contig1061_RC KIAA0924 proteinHypothetical protein, Metal-binding, 499 4467 Nuclear protein, Zinc,Zinc-finger Contig10629_RC PERQ1 PERQ amino acid Hypothetical protein500 4468 rich, with GYF domain 1 Contig1063_RC TRIM33 Homo sapiens cDNAHypothetical protein 501 4469 FLJ35131 fis, clone PLACE6008824.Contig10670_RC Transcribed 502 4470 sequences Contig10690_RC spleentyrosine Transferase, Tyrosine-protein 503 4471 kinase kinase,ATP-binding, Phosphorylation, SH2 domain, Repeat, Alternative splicing,3D- structure Contig10750_RC Transcribed 504 4472 sequencesContig10844_RC CDNA FLJ31150 fis, Hypothetical protein 505 4473 cloneIMR322001534 Contig11012_RC leukocyte-derived Aminopeptidase 506 4474arginine aminopeptidase Contig11075_RC NFASC neurofascin Cell adhesion,Repeat, Signal, 507 4475 Transmembrane, Immunoglobulin domain,Glycoprotein, Alternative splicing, Polymorphism, Hypothetical proteinContig11266_RC Transcribed 508 4476 sequence with moderate similarity toprotein ref: NP_054848.1 (H. sapiens) PRO0478 protein [Homo sapiens]Contig112_RC NICE-4 NICE-4 protein Hypothetical protein 509 4477Contig1146_RC LOC90550 chromosome 10 Hypothetical protein 510 4478 openreading frame 42 Contig11_RC hypothetical protein Hypothetical protein511 4479 LOC90462 Contig12140_RC Transcribed 512 4480 sequencesContig12201_RC splicing factor, Nuclear protein, RNA-binding, 513 4481arginine/serine-rich 5 mRNA splicing, Alternative splicing, Repeat,Phosphorylation, Polymorphism, Plasmid Contig12540_RC Transcribed 5144482 sequences Contig12750_RC hypothetical protein Hypothetical protein515 4483 LOC257106 Contig12755_RC GCN1L1 homeodomain Transferase,Serine/threonine- 516 4484 interacting protein protein kinase,ATP-binding, Nuclear kinase 2 protein, Alternative splicingContig12820_RC FLJ21709 nucleotide-binding Hypothetical protein 517 4485oligomerization domains 27 Contig12855 MAPK8IP2 MRNA; cDNA Kinase, SH3domain, Alternative 518 4486 DKFZp434J0428 splicing (from cloneDKFZp434J0428) Contig1295_RC MDS033 protein F25965 Transmembrane, Golgistack, 519 4487 Endoplasmic reticulum Contig13165_RC B4GALT6 UDP-Transferase, Glycosyltransferase, 520 4488 Gal:betaGlcNAc Glycoprotein,Transmembrane, beta 1,4- Signal-anchor, Golgi stack,galactosyltransferase, Manganese, Magnesium, Calcium, polypeptide 6Multigene family Contig13387_RC FLJ21458 hypothetical proteinHypothetical protein 521 4489 FLJ21458 Contig13480_RC Transcribed 5224490 sequences Contig1351_RC zinc finger protein Hypothetical protein,Metal-binding, 523 4491 325 Nuclear protein, Zinc, Zinc-finger,Transcription regulation, DNA- binding, Repeat Contig13609_RCTranscribed 524 4492 sequences Contig13643_RC Transcribed 525 4493sequences Contig1366_RC DC-TM4F2 tetraspanin similar to Hypotheticalprotein, 526 4494 TM4SF9 Transmembrane Contig13766_RC Transcribed 5274495 sequences Contig1386_RC SEMA4B sema domain, Transmembrane,Immunoglobulin 528 4496 immunoglobulin domain, Multigene family, domain(Ig), Neurogenesis, Developmental transmembrane protein, Glycoprotein,Signal, domain (TM) and Polymorphism short cytoplasmic domain,(semaphorin) 4B Contig1389_RC ITPR1 mitogen-activated ATP-binding,Kinase, Transferase, 529 4497 protein kinase 9 Serine/threonine-proteinkinase, Phosphorylation, Alternative splicing Contig14039_RC FOXE3forkhead box E3 Transcription regulation, DNA- 530 4498 binding, Nuclearprotein Contig1403_RC LBH likely ortholog of Hypothetical protein 5314499 mouse limb-bud and heart gene Contig14172 vitelliform macular Ironstorage, Iron, Metal-binding, 3D- 532 4500 dystrophy (Best structure,Transport, Ion transport, disease, bestrophin) Ionic channel, Chloridechannel, Calcium, Alternative splicing, Disease mutation, Polymorphism,Vision, Transmembrane, Phosphorylation Contig14197_RC Transcribed 5334501 sequences Contig1422_RC hypothetical protein Hypothetical protein534 4502 FLJ38426 Contig14282_RC Transcribed 535 4503 sequencesContig14433_RC Transcribed 536 4504 sequences Contig1447_RC EFG1mitochondrial Elongation factor, Protein 537 4505 elongation factor G1biosynthesis, Mitochondrion, Transit peptide, GTP-binding Contig14520_RCTranscribed 538 4506 sequences Contig14555_RC Transcribed 539 4507sequences Contig14581_RC Transcribed 540 4508 sequences Contig14625_RCFLJ22021 hypothetical protein Repeat, WD repeat 541 4509 FLJ22021Contig1462_RC C11orf15 chromosome 11 Transmembrane 542 4510 open readingframe 15 Contig14658_RC zx08b09.s1 543 4511 Soares_total_fetus_Nb2HF8_9wHomo sapiens cDNA clone IMAGE: 785849 3′, mRNA sequence. Contig14720_RCTranscribed 544 4512 sequences Contig14797_RC Transcribed 545 4513sequences Contig14899_RC LOC146853 LOC146853 546 4514 Contig1505_RCMGC4308 hypothetical protein 547 4515 MGC4308 Contig151_RC ELKS CDNAFLJ31750 fis, Hypothetical protein 548 4516 clone NT2RI2007406Contig15267_RC Transcribed 549 4517 sequences Contig15281_RCChediak-Higashi Protein transport, Transport, Repeat, 550 4518 syndrome1 WD repeat, Disease mutation, Alternative splicing Contig1540_RC ACTBserine Transferase, Acyltransferase, 551 4519 palmitoyltransferase,Transmembrane, Pyridoxal long chain base phosphate, Endoplasmicreticulum subunit 2 Contig15580_RC LOC401124 552 4520 (LOC401124), mRNAContig15607_RC Transcribed 553 4521 sequences Contig15635_RC Transcribed554 4522 sequences Contig15647_RC Transcribed 555 4523 sequencesContig15674_RC Transcribed 556 4524 sequences Contig15898_RC Transcribed557 4525 sequence with weak similarity to protein ref: NP_055301.1 (H.sapiens) neuronal thread protein [Homo sapiens] Contig16192_RCTranscribed 558 4526 sequence with moderate similarity to protein ref:NP_110386.1 (H. sapiens) nuclear receptor binding factor-2 [Homosapiens] Contig1619_RC NAPB N-ethylmaleimide- Hypothetical protein 5594527 sensitive factor attachment protein, beta Contig1620_RC PPP1R16Aprotein phosphatase ANK repeat, Repeat, Coiled coil, 560 4528 1,regulatory Lipoprotein, Prenylation, Membrane (inhibitor) subunit 16AContig16217_RC Transcribed 561 4529 sequences Contig1632_RC MGC17921chromosome 14 Alternative splicing 562 4530 open reading frame 31Contig16376_RC DKFZP564B1162 hypothetical protein Hypothetical protein563 4531 DKFZp564B1162 Contig16437_RC Transcribed 564 4532 sequencesContig16440_RC Transcribed 565 4533 sequences Contig16441_RC Transcribed566 4534 sequences Contig16447_RC C16orf44 chromosome 16 Hypotheticalprotein 567 4535 open reading frame 44 Contig16530_RC Transcribed 5684536 sequences Contig16736_RC Clone Hypothetical protein 569 4537 IMAGE:5561763, mRNA Contig16772_RC Transcribed 570 4538 sequencesContig16786_RC Transcribed 571 4539 sequences Contig1682_RC RCP Rabcoupling protein Hypothetical protein 572 4540 Contig16908_RC MGC42174hypothetical protein Hypothetical protein 573 4541 MGC42174Contig16931_RC YR-29 TGF beta-inducible Nuclear protein 574 4542 nuclearprotein 1 Contig1699_RC FLJ12438 hypothetical protein Hypotheticalprotein 575 4543 FLJ12438 Contig17017_RC Transcribed 576 4544 sequencesContig17084_RC DEAD (Asp-Glu-Ala- ATP-binding, Helicase, Hydrolase, 5774545 Asp) box polypeptide Hypothetical protein 31 Contig17109_RC Similarto Protein 578 4546 C20orf27 (LOC390690), mRNA Contig17356_RChypothetical protein Hypothetical protein 579 4547 FLJ13611Contig17607_RC Transcribed 580 4548 sequences Contig1789_RC LAGYhomeodomain-only Hypothetical protein, DNA-binding, 581 4549 proteinHomeobox, Nuclear protein Contig178_RC syntrophin, beta 2 Actin-binding,Cytoskeleton, 582 4550 (dystrophin- Microtubule, Calcium-binding,associated protein Calmodulin-binding, Membrane, A1, 59 kDa, basicPhosphorylation, Repeat, component 2) Polymorphism, Multigene family,Alternative splicing Contig17982_RC hypothetical protein Hypotheticalprotein 583 4551 FLJ14624 Contig1798_RC MOX2 antigen identified byAntigen, Neurone, T-cell, Signal, 584 4552 monoclonal antibodyTransmembrane, Immunoglobulin MRC OX-2 domain, Glycoprotein, Alternativesplicing Contig18246_RC oz78a12.x1 585 4553Soares_senescent_fibroblasts_NbHSF Homo sapiens cDNA clone IMAGE:1681438 3′, mRNA sequence. Contig18286_RC pellino 3 alpha Alternativesplicing 586 4554 Contig18476_RC Homo sapiens, clone 587 4555 IMAGE:4830091, mRNA. Contig18493_RC oj35b09.s1 588 4556 NCI_CGAP_Lu5 Homosapiens cDNA clone IMAGE: 1500281 3′, mRNA sequence. Contig18504_RCOR52K3P olfactory receptor, Hypothetical protein 589 4557 family 52,subfamily K, member 3 pseudogene Contig19023_RC yf45a10.s2 Soares 5904558 fetal liver spleen 1NFLS Homo sapiens cDNA clone IMAGE: 129786 3′,mRNA sequence. Contig19064_RC hypothetical protein 591 4559 LOC340351Contig19127_RC FLJ31295 hypothetical protein Metal-binding, Zinc,Zinc-finger, 592 4560 FLJ31295 Hypothetical protein Contig19210_RCTranscribed 593 4561 sequences Contig1924_RC C20orf11 chromosome 20Coiled coil 594 4562 open reading frame 11 Contig19333_RC Transcribed595 4563 sequences Contig1951 GNPAT MRNA; cDNA Transferase,Acyltransferase, 596 4564 DKFZp686J23256 Peroxisome, Membrane,Rhizomelic (from clone chondrodysplasia punctata, DiseaseDKFZp686J23256) mutation Contig19700_RC Transcribed 597 4565 sequencesContig19715_RC Transcribed 598 4566 sequences Contig1990_RC LOC92799hypothetical protein Repeat, WD repeat, Hypothetical 599 4567 BC007653protein Contig19918_RC Transcribed 600 4568 sequences Contig1991_RC PGA5pepsinogen 5, group Hydrolase, Aspartyl protease, 601 4569 I (pepsinogenA) Digestion, Zymogen, Signal, Phosphorylation, 3D-structure,Polymorphism Contig19931_RC Transcribed 602 4570 sequencesContig20370_RC Transcribed 603 4571 sequences Contig20391_RC Transcribed604 4572 sequence with strong similarity to protein pir: EFHU1 (H.sapiens) EFHU1 translation elongation factor eEF-1 alpha-1 chain - humanContig20427_RC Transcribed 605 4573 sequences Contig20600_RC CDNAFLJ34654 fis, 606 4574 clone KIDNE2018294 Contig20617_RC CDNA FLJ34031fis, 607 4575 clone FCBBF2003895 Contig20830_RC Homo sapiens cDNA 6084576 FLJ13550 fis, clone PLACE1007111. Contig20843_RC Transcribed 6094577 sequences Contig20864_RC FLJ22529 hypothetical protein Hypotheticalprotein 610 4578 FLJ22529 Contig20913_RC FLJ12785 hypothetical proteinHypothetical protein 611 4579 FLJ12785 Contig20979_RC hypotheticalprotein 612 4580 MGC35555 Contig21098_RC Msx-interacting-zinc Multigenefamily, Zinc-finger, 613 4581 finger Nuclear protein, DNA-binding,Metal- binding, Alternative splicing Contig21116_RC Transcribed 614 4582sequences Contig21200_RC Transcribed 615 4583 sequences Contig21268_RCSimilar to 616 4584 hypothetical protein FLJ35867 (LOC342357), mRNAContig2143_RC KIAA1771 dedicator of Hypothetical protein, Guanine- 6174585 cytokinesis 7 nucleotide releasing factor, Alternative splicingContig21627_RC CDNA FLJ39637 fis, Hypothetical protein 618 4586 cloneSMINT2003003 Contig21787_RC Transcribed 619 4587 sequences Contig2179_RCFLJ32452 hypothetical protein Hypothetical protein 620 4588 FLJ32452Contig21839_RC ow70g11.s1 621 4589 Soares_fetal_liver_spleen_1NFLS_S1Homo sapiens cDNA clone IMAGE: 1652228 3′, mRNA sequence. Contig21847_RCKSP37 Ksp37 protein 622 4590 Contig21891_RC FLJ13231 hypotheticalprotein Hypothetical protein 623 4591 FLJ13231 Contig21904immunoglobulin 624 4592 superfamily, member 2 Contig21997_RC Transcribed625 4593 sequences Contig22003_RC Transcribed 626 4594 sequencesContig22025_RC FLJ10111 v-akt murine Hypothetical protein, ATP-binding,627 4595 thymoma viral Transferase, Serine/threonine- oncogene homolog 1protein kinase, Phosphorylation, Nuclear protein, Kinase Contig22418_RCPTP4A3 protein tyrosine 628 4596 phosphatase type IVA, member 3Contig22526_RC Transcribed 629 4597 sequences Contig22551_RC Transcribed630 4598 sequences Contig2263_RC KIAA1949 KIAA1949 Hypothetical protein631 4599 Contig22844_RC DKFZp434H2111 hypothetical protein Hypotheticalprotein 632 4600 DKFZp434H2111 Contig22901_RC AGENCOURT_6640943 633 4601NIH_MGC_99 Homo sapiens cDNA clone IMAGE: 5434077 5′, mRNA sequence.Contig23240_RC hypothetical protein Hypothetical protein 634 4602FLJ12525 Contig23263_RC NR5A1 Homo sapiens cDNA Receptor, Transcriptionregulation, 635 4603 FLJ33539 fis, clone DNA-binding, Nuclear protein,Zinc- BRAMY2007610, finger, Disease mutation, highly similar toHypothetical protein STEROIDOGENIC FACTOR 1. Contig23280lecithin-cholesterol Cholesterol metabolism, Lipid 636 4604acyltransferase metabolism, Transferase, Acyltransferase, Signal,Glycoprotein, Polymorphism, Disease mutation Contig23299_RC P5 BTG3associated Hypothetical protein 637 4605 nuclear protein Contig2339_RCFLJ21032 stearoyl-CoA Hypothetical protein 638 4606 desaturase 4Contig23423_RC Transcribed 639 4607 sequences Contig23525_RC KIAA0140similar to CG9643- Hypothetical protein 640 4608 PA Contig23547_RC Clone641 4609 IMAGE: 5214442, mRNA Contig23593_RC Transcribed 642 4610sequences Contig23604_RC carnitine O- Transferase, Acyltransferase,Fatty 643 4611 octanoyltransferase acid metabolism, Transport,Peroxisome Contig23667_RC WD repeat and Nuclear protein, DNA-binding,644 4612 HMG-box DNA Repeat, WD repeat binding protein 1 Contig24090CDNA FLJ37425 fis, 645 4613 clone BRAWH2001530 Contig24094_RC CDNAFLJ30598 fis, 646 4614 clone BRAWH2009263 Contig24098_RC glutamatereceptor, Receptor, Signal, Transmembrane, 647 4615 ionotropic, N-methylPostsynaptic membrane, Calcium, D-aspartate 2D Glycoprotein, Ionicchannel, Magnesium Contig2429_RC FLJ40142 protein Hypothetical protein648 4616 Contig24450_RC Transcribed 649 4617 sequences Contig24453_RCTranscribed 650 4618 sequences Contig24600_RC Transcribed 651 4619sequences Contig25041_RC yx89b03.s1 Soares 652 4620 melanocyte 2NbHMHomo sapiens cDNA clone IMAGE: 268877 3′, mRNA sequence. Contig25058_RCTranscribed 653 4621 sequences Contig2505_RC GLTP glycolipid transferTransport, Lipid transport, Repeat, 654 4622 protein AcetylationContig25107_RC ferredoxin 1 Metal-binding, Iron-sulfur, Iron, 2Fe—2S,655 4623 Electron transport, Mitochondrion, Transit peptideContig25126_RC Transcribed 656 4624 sequences Contig2531_RC FLJ12484hypothetical protein Hypothetical protein 657 4625 FLJ12484Contig25332_RC GDF11 cytokine induced Nuclear protein, DNA-binding, 6584626 protein 29 kDa Transcription, Transcription regulation, Translationregulation Contig25362_RC DKFZP566A1524 hypothetical proteinHypothetical protein 659 4627 DKFZp566A1524 Contig25429_RC Transcribed660 4628 sequences Contig25435_RC FLJ10803 hypothetical proteinHypothetical protein 661 4629 FLJ10803 Contig2544 FLJ11526 hypotheticalprotein Hypothetical protein 662 4630 FLJ11526 Contig25546_RC CCT6Aitchy homolog E3 Ubl conjugation pathway, Ligase, 663 4631 ubiquitinprotein Nuclear protein, Repeat, ligase (mouse) Phosphorylation,Alternative splicing Contig25595_RC KIAA1618 KIAA1618 Hypotheticalprotein 664 4632 Contig256 PSMD11 wt73b11.x1 Proteasome 665 4633Soares_thymus_NHFTh Homo sapiens cDNA clone IMAGE: 2513085 3′ similar toTR: Q26195 Q26195 PVA1 GENE.; mRNA sequence. Contig25610_RC CDNAFLJ31796 fis, 666 4634 clone NT2RI2008841 Contig25744_RC Transcribed 6674635 sequences Contig2576_RC DKFZP564O1664 hypothetical proteinHypothetical protein 668 4636 DKFZp564O1664 Contig25770_RC Clone 6694637 IMAGE: 4817413, mRNA Contig25783_RC Clone 670 4638 IMAGE: 5555626,mRNA Contig2578_RC ORF1-FL49 putative nuclear Nuclear protein 671 4639protein ORF1-FL49 Contig25827_RC FLJ13848 hypothetical proteinHypothetical protein 672 4640 FLJ13848 Contig2584_RC ribonuclease PHydrolase, Nuclear protein, tRNA 673 4641 (14 kD) processingContig25861_RC Transcribed 674 4642 sequences Contig25960_RCDKFZP564B0769 chromosome 6 open Hypothetical protein 675 4643 readingframe 111 Contig26014_RC SYTL3 synaptotagmin-like 3 676 4644Contig26019_RC methionyl Aminopeptidase, Hypothetical 677 4645aminopeptidase 2 protein, Hydrolase, Cobalt, 3D- structureContig26059_RC Transcribed 678 4646 sequences Contig2608 SLC2A4RG SLC2A4regulator Transcription regulation, DNA- 679 4647 binding, Nuclearprotein, Zinc-finger, Metal-binding, Alternative splicing Contig26170_RCTranscribed 680 4648 sequences Contig26332_RC Transcribed 681 4649sequences Contig263_RC MGC12435 chromosome 14 682 4650 open readingframe 168 Contig26405_RC TSLL2 immunoglobulin Immunoglobulin domain 6834651 superfamily, member 4C Contig26416_RC Transcribed 684 4652sequences Contig26461_RC Transcribed 685 4653 sequences Contig2647_RCBCAT1 branched chain Transferase, Aminotransferase, 686 4654aminotransferase 1, Hypothetical protein, Branched-chain cytosolic aminoacid biosynthesis, Pyridoxal phosphate Contig2648_RC MGC15407 similar toRIKEN 687 4655 cDNA 4931428D14 gene Contig2657_RC MGC16207 hypotheticalprotein Hypothetical protein 688 4656 MGC16207 Contig26622_RC BIC BICtranscript 689 4657 Contig26706_RC CDNA FLJ43676 fis, 690 4658 cloneSYNOV4009129 Contig26998_RC WD repeat domain 1 Repeat, WD repeat,Actin-binding, 691 4659 Cytoskeleton, Alternative splicing,Polymorphism, Hypothetical protein Contig27060_RC Transcribed 692 4660sequence with moderate similarity to protein pdb: 1LBG (E. coli) B ChainB, Lactose Operon Repressor Bound To 21-Base Pair Symmetric OperatorDna, Alpha Carbons Only Contig27084_RC CDNA FLJ45493 fis, 693 4661 cloneBRTHA2008598 Contig27124_RC CDNA FLJ42250 fis, 694 4662 cloneTKIDN2007828 Contig27145_RC Transcribed 695 4663 sequencesContig27228_RC amyloid beta (A4) Hypothetical protein 696 4664 precursorprotein- binding, family B, member 1 interacting protein Contig2728_RCzinc finger protein Hypothetical protein, Metal-binding, 697 4665 596Zinc, Zinc-finger Contig27338_RC Transcribed 698 4666 sequencesContig27386_RC C7orf13 chromosome 7 open 699 4667 reading frame 13Contig27542_RC Transcribed 700 4668 sequences Contig27558_RC FLJ13163MRNA; cDNA Hypothetical protein, Kinase 701 4669 DKFZp779J2459 (fromclone DKFZp779J2459) Contig27725_RC Transcribed 702 4670 sequencesContig27765_RC potassium inwardly- Hypothetical protein, Ionic channel,703 4671 rectifying channel, Ion transport, Voltage-gated subfamily J,member channel, Transmembrane, 15 Potassium transport Contig27776_RChypothetical protein Hypothetical protein 704 4672 FLJ21106Contig27797_RC DnaJ (Hsp40) Chaperone, Repeat, Zinc, Metal- 705 4673homolog, subfamily binding, Prenylation, Lipoprotein, A, member 2Membrane, Multigene family Contig27820_RC Transcribed 706 4674 sequencesContig27837_RC Transcribed 707 4675 sequence with weak similarity toprotein ref: NP_060265.1 (H. sapiens) hypothetical protein FLJ20378[Homo sapiens] Contig27896_RC HSPC009 protein 708 4676 Contig27915_RCMGC40042 hypothetical protein Hypothetical protein 709 4677 MGC40042Contig27977_RC Transcribed 710 4678 sequences Contig28024_RC KIAA0955caspase recruitment Apoptosis, Nuclear protein, 711 4679 domain family,Alternative splicing, Hypothetical member 8 protein Contig28050_RC Homosapiens cDNA 712 4680 FLJ35764 fis, clone TESTI2004906, weakly similarto H. sapiens mRNA for SIRP-beta1. Contig2811_RC C8orf2 Homo sapiensTransmembrane, Alternative splicing 713 4681 mRNA; cDNA DKFZp667H242(from clone DKFZp667H242); complete cds. Contig28164_RC Transcribed 7144682 sequences Contig28181_RC ns17h07.s1 715 4683 NCI_CGAP_GCB1 Homosapiens cDNA clone IMAGE: 1183933 3′, mRNA sequence. Contig28229_RCTranscribed 716 4684 sequences Contig2823_RC FLJ23499 chromosome 11Hypothetical protein 717 4685 open reading frame 1 Contig28286_RCTranscribed 718 4686 sequences Contig28298_RC NUP62 UI-H-BI0p-abm-b-Nuclear protein, Transport, 719 4687 04-0-UI.s1 Glycoprotein, Coiledcoil, Repeat, NCI_CGAP_Sub2 Polymorphism Homo sapiens cDNA clone IMAGE:2712150 3′, mRNA sequence. Contig28522_RC Clone 24653 mRNA 720 4688sequence Contig28567_RC Transcribed 721 4689 sequences Contig2857_RCDKFZp761G2113 hypothetical protein Hypothetical protein 722 4690DKFZp761G2113 Contig28707_RC ADAMTS13 a disintegrin-like and Protease,Hypothetical protein, 723 4691 metalloprotease Signal (reprolysin type)with thrombospondin type 1 motif, 13 Contig28760_RC cyclin-dependent 7244692 kinase 6 Contig28766_RC Transcribed 725 4693 sequencesContig28787_RC hypothetical protein Hypothetical protein 726 4694LOC120526 Contig2883_RC RALY Clone Ribonucleoprotein, RNA-binding, 7274695 IMAGE: 5285100, Nuclear protein, Antigen, Alternative mRNAsplicing, Polymorphism Contig28947_RC CDC25A cell division cycle Celldivision, Mitosis, Hydrolase, 728 4696 25A Alternative splicing,Multigene family, 3D-structure, Hypothetical protein Contig28949 Clone729 4697 IMAGE: 5268292, mRNA Contig28996_RC NHL repeat 730 4698containing 1 Contig29171_RC CDNA FLJ11544 fis, 731 4699 cloneHEMBA1002826 Contig29207_RC chromosome 20 732 4700 open reading frame 78Contig29284_RC Transcribed 733 4701 sequences Contig292_RC FLJ22386leucine zipper Hypothetical protein 734 4702 domain proteinContig2930_RC DAB2 CDNA FLJ35517 fis, Alternative splicing,Phosphorylation 735 4703 clone SPLEN2000698 Contig29349_RC Transcribed736 4704 sequences Contig29362_RC hypothetical protein Hypotheticalprotein 737 4705 LOC338692 Contig29373_RC 24b2/STAC2 protein 738 4706Contig29569_RC hypothetical protein Hypothetical protein 739 4707MGC29898 Contig29732_RC hypothetical protein 740 4708 LOC338758Contig29749_RC LOC85028 PNAS-123 741 4709 Contig29780_RC Transcribed 7424710 sequences Contig29802_RC programmed cell Calcium-binding, Repeat,Apoptosis 743 4711 death 6 Contig29860_RC NFAM1 NFAT activationHypothetical protein, Signal, 744 4712 molecule 1 Transmembrane,Immunoglobulin domain, Phosphorylation Contig2986_RC EEG1 C1q domainHypothetical protein 745 4713 containing 1 Contig29887_RC DKFZp434J0617hypothetical protein Hypothetical protein 746 4714 DKFZp434J0617Contig29890_RC FLJ32449 ankyrin repeat Hypothetical protein, ANK repeat,747 4715 domain 23 Repeat Contig29901_RC proteasome Proteasome,Hydrolase, Protease, 748 4716 (prosome, Acetylation, Alternativesplicing, macropain) subunit, Phosphorylation, Threonine protease alphatype, 3 Contig29921_RC FLJ22570 Dok-like protein Hypothetical protein749 4717 Contig29940_RC CMYA1 cardiomyopathy Hypothetical protein 7504718 associated 1 Contig29954_RC CATSPER2 Clone 751 4719 IMAGE: 5294645,mRNA Contig29955_RC zj86d08.s1 752 4720Soares_fetal_liver_spleen_1NFLS_S1 Homo sapiens cDNA clone IMAGE: 4617753′, mRNA sequence. Contig29995_RC Transcribed 753 4721 sequencesContig30052_RC C18B11 C18B11 homolog Hypothetical protein 754 4722 (44.9kD) Contig30109_RC PRKWNK4 protein kinase, lysine Hypothetical protein,ATP-binding, 755 4723 deficient 4 Transferase, Kinase,Serine/threonine-protein kinase Contig30154_RC Transcribed 756 4724sequence with moderate similarity to protein sp: P39194 (H. sapiens)ALU7_HUMAN Alu subfamily SQ sequence contamination warning entryContig3015_RC pleckstrin homology 757 4725 domain containing, family A(phosphoinositide binding specific) member 2 Contig30209_RC FLJ12649hypothetical protein Hypothetical protein 758 4726 FLJ12649Contig30378_RC FLJ10178 hypothetical protein Hypothetical protein 7594727 FLJ10178 Contig30474_RC VIT vitrin Hypothetical protein 760 4728Contig30484_RC Transcribed 761 4729 sequences Contig30496_RC ZNF219LOC400176 Transcription regulation, DNA- 762 4730 (LOC387957), binding,Zinc-finger, Metal-binding, mRNA Nuclear protein, Repeat Contig30736_RCTranscribed 763 4731 sequences Contig30811_RC PRKRA MRNA; cDNA Kinase764 4732 DKFZp686G1498 (from clone DKFZp686G1498) Contig30840_RCLOC63929 hypothetical protein Hypothetical protein 765 4733 LOC63929Contig30934_RC MGC33993 hypothetical protein Hypothetical protein,Metal-binding, 766 4734 MGC33993 Zinc, Zinc-finger Contig3094_RC PINK1PTEN induced Hypothetical protein, ATP-binding, 767 4735 putative kinase1 Kinase, Serine/threonine-protein kinase, Transferase Contig30977_RChypothetical protein 768 4736 LOC154790 Contig30989_RC MGC10744hypothetical protein Hypothetical protein 769 4737 MGC10744Contig31057_RC Transcribed 770 4738 sequences Contig31186_RC HNRPDLheterogeneous Nucleocapsid, Ribonucleoprotein 771 4739 nuclearribonucleoprotein D- like Contig31361_RC dedicator of Hypotheticalprotein, Guanine- 772 4740 cytokinesis 7 nucleotide releasing factor,Alternative splicing Contig31366_RC LNPEP hypothetical proteinHypothetical protein 773 4741 FLJ39485 Contig31421_RC thyroid hormoneProteasome, Ubl conjugation 774 4742 receptor interactor pathway, Ligase12 Contig31449_RC Transcribed 775 4743 sequence with weak similarity toprotein sp: P39195 (H. sapiens) ALU8_HUMAN Alu subfamily SX sequencecontamination warning entry Contig3147_RC MUM2 trafficking proteinTransport, Endoplasmic reticulum, 776 4744 particle complex 1 Golgistack, Disease mutation Contig31482_RC Transcribed 777 4745 sequencesContig31495 thyroid hormone Antigen, Golgi stack, Coiled coil, 778 4746receptor interactor Chromosomal translocation, 11 Hypothetical proteinContig31513_RC Transcribed 779 4747 sequences Contig31525_RC Transcribed780 4748 sequence with weak similarity to protein ref: NP_079364.1 (H.sapiens) hypothetical protein FLJ13241 [Homo sapiens] Contig31587_RCHuman full-length Plasmid 781 4749 cDNA 5-PRIME end of cloneCS0DK007YB08 of HeLa cells of Homo sapiens (human) Contig31597_RCPDE4DIP chromosome 1 Hypothetical protein 782 4750 amplified sequence 3Contig31661_RC hypothetical protein Hypothetical protein, Repeat, WD 7834751 FLJ10385 repeat Contig31664_RC MGC26979 hypothetical proteinHypothetical protein 784 4752 MGC26979 Contig31699_RC CDNA FLJ27273 fis,785 4753 clone TMS00761 Contig31740_RC PFN1 hypothetical proteinMetal-binding, Zinc, Zinc-finger, 786 4754 LOC285345 Transcriptionregulation, DNA- binding, Nuclear protein, Repeat Contig31864_RC FERMdomain Hypothetical protein 787 4755 containing 3 Contig31906_RC similarto Hypothetical protein 788 4756 hypothetical protein FLJ13659Contig31911_RC hypothetical protein Hypothetical protein 789 4757LOC349136 Contig32027_RC CDNA FLJ46867 fis, 790 4758 clone UTERU3012293,weakly similar to Homo sapiens zinc finger protein 14 (KOX 6) (ZNF14)Contig32059_RC MGC17919 zinc finger and BTB Zinc, Hypothetical protein,Metal- 791 4759 domain containing 8 binding, Zinc-finger Contig32081_RCFull length insert 792 4760 cDNA clone YP77A07 Contig32103_RC Clone 7934761 IMAGE: 4689481, mRNA Contig32123_RC Similar to ataxin 2 794 4762binding protein 1 isoform gamma; hexaribonucleotide binding protein 1(LOC339162), mRNA Contig32185_RC intimal thickness- 795 4763 relatedreceptor Contig3228_RC VMP1 hypothetical protein Hypothetical protein796 4764 LOC283680 Contig32322_RC quaking homolog, Hypothetical protein797 4765 KH domain RNA binding (mouse) Contig32323_RC hypotheticalprotein Hypothetical protein 798 4766 FLJ13105 Contig32335_RCTranscribed 799 4767 sequences Contig32377_RC ubiquitin specificProtease 800 4768 protease 51 Contig32431_RC Transcribed 801 4769sequences Contig3250_RC LOC92399 mitochondrial Hypothetical protein 8024770 ribosome recycling factor Contig32540_RC Transcribed 803 4771sequences Contig32550_RC ZFP93 zinc finger protein Transcriptionregulation, DNA- 804 4772 235 binding, Zinc-finger, Metal-binding,Nuclear protein, Repeat Contig32637_RC RAB27A, member GTP-binding,Lipoprotein, 805 4773 RAS oncogene Prenylation, Alternative splicing,family Disease mutation Contig32757 FLJ21069 hypothetical proteinHypothetical protein, ANK repeat, 806 4774 FLJ21069 RepeatContig32825_RC polymerase (RNA) III 807 4775 (DNA directed) (32 kD)Contig32920 FUBP1 nexilin (F actin Hypothetical protein 808 4776 bindingprotein) Contig33062_RC chromosome 17 Hypothetical protein 809 4777 openreading frame 31 Contig3311_RC MGC13186 hypothetical proteinHypothetical protein, ATP-binding 810 4778 MGC13186 Contig33127_RCSequence 161 from 811 4779 Patent WO0220754. Contig3313 FLJ23153 likelyortholog of Hypothetical protein 812 4780 mouse tumor necrosis-alpha-induced adipose- related protein Contig33188_RC Transcribed 813 4781sequences Contig33207_RC Transcribed 814 4782 sequences Contig33224_RCTranscribed 815 4783 sequences Contig33273_RC chromodomain DNA-binding,Helicase, Hypothetical 816 4784 helicase DNA protein, ATP-binding,Hydrolase binding protein 1-like Contig3331_RC MKI67IP MKI67 (FHA 8174785 domain) interacting nucleolar phosphoprotein Contig33334_RCTranscribed 818 4786 sequences Contig33369_RC Transcribed 819 4787sequence with weak similarity to protein ref: NP_062553.1 (H. sapiens)hypothetical protein FLJ11267 [Homo sapiens] Contig33394_RC FLJ37318ubiquitin specific Hypothetical protein 820 4788 protease 54 Contig3344MGC2835 DEAD (Asp-Glu-Ala- ATP-binding, Helicase, Hydrolase, 821 4789Asp) box polypeptide Hypothetical protein 54 Contig33442_RC MOB1, MpsOne Hypothetical protein 822 4790 Binder kinase activator-like 2A(yeast) Contig33464_RC Similar to bA304I5.1 823 4791 (novel lipase)(LOC340654), mRNA Contig33540_RC SEMA3F ob92d09.s1 Signal,Immunoglobulin domain, 824 4792 NCI_CGAP_GCB1 Multigene family,Glycoprotein, Homo sapiens cDNA Polymorphism clone IMAGE: 1338833 3′,mRNA sequence. Contig33574_RC Transcribed 825 4793 sequencesContig3359_RC neuralized-like Hypothetical protein 826 4794 (Drosophila)Contig33703_RC FLJ21438 hypothetical protein Hypothetical protein 8274795 FLJ21438 Contig33741_RC FLJ12428 DEP domain Hypothetical protein828 4796 containing 6 Contig33760_RC chromosome 9 open 829 4797 readingframe 71 Contig33790_RC jun dimerization DNA-binding, Nuclear protein830 4798 protein 2 Contig33810_RC FLJ31528 hypothetical proteinHypothetical protein 831 4799 FLJ31528 Contig33831_RC Transcribed 8324800 sequences Contig33852_RC OPRL1 opiate receptor-like 1 G-proteincoupled receptor, 833 4801 Transmembrane, Glycoprotein, Phosphorylation,Lipoprotein, Palmitate, Alternative splicing Contig33888_RC ow44c09.x1834 4802 Soares_parathyroid_tumor_NbHPA Homo sapiens cDNA clone IMAGE:1649680 3′, mRNA sequence. Contig3390_RC FLJ12619 chromosome 6 openHypothetical protein 835 4803 reading frame 62 Contig33951_RC nuclearpore Nuclear protein, Transport 836 4804 complex protein Contig33967_RCTranscribed 837 4805 sequences Contig33987 hypothetical proteinHypothetical protein 838 4806 KIAA1109 Contig33996_RC Transcribed 8394807 sequences Contig34019_RC MGC15827 hypothetical protein Hypotheticalprotein 840 4808 MGC15827 Contig34051_RC Transcribed 841 4809 sequencesContig34090_RC Transcribed 842 4810 sequences Contig340_RC PPP1R15Bprotein phosphatase Hypothetical protein 843 4811 1, regulatory(inhibitor) subunit 15B Contig34118_RC Transcribed 844 4812 sequencesContig34231_RC yd77f12.s1 Soares 845 4813 fetal liver spleen 1NFLS Homosapiens cDNA clone IMAGE: 114287 3′, mRNA sequence. Contig34286_RCTranscribed 846 4814 sequences Contig34291_RC nuclear receptorTranscription regulation, Receptor, 847 4815 subfamily 3, groupTrans-acting factor, Nuclear protein, C, member 1 DNA-binding,Steroid-binding, Zinc- (glucocorticoid finger, Phosphorylation, Ublreceptor) conjugation, Alternative initiation, Alternative splicing,Polymorphism, Disease mutation Contig34302_RC hypothetical protein 8484816 LOC150166 Contig34303_RC SFXN5 sideroflexin 5 Transport, Irontransport, Iron, 849 4817 Mitochondrion, Transmembrane Contig34350_RCCDNA FLJ45384 fis, 850 4818 clone BRHIP3021987 Contig34470_RC similar tokinesin Hypothetical protein 851 4819 family member 21A; N-5 kinesinContig34554_RC CDNA FLJ33367 fis, 852 4820 clone BRACE2005661Contig34593_RC Transcribed 853 4821 sequences Contig34607_RC ym49g02.s1Soares 854 4822 infant brain 1NIB Homo sapiens cDNA clone IMAGE: 515863′, mRNA sequence. Contig34634_RC GCN1L1 homeodomain Transferase,Serine/threonine- 855 4823 interacting protein protein kinase,ATP-binding, Nuclear kinase 2 protein, Alternative splicingContig34672_RC Transcribed 856 4824 sequences Contig3474_RC CDNA:FLJ22541 857 4825 fis, clone HSI00130 Contig34768_RC chromosome 21Hypothetical protein 858 4826 open reading frame 59 Contig34779_RCSH3-domain kinase SH3 domain, Repeat, Membrane, 859 4827 binding protein1 Nuclear protein, Coiled coil, Polymorphism, Alternative splicingContig34880_RC Transcribed 860 4828 sequences Contig3495_RC MGC45416hypothetical protein Hypothetical protein 861 4829 MGC45416Contig34983_RC Transcribed 862 4830 sequences Contig34998_RC TMLHE CDNAFLJ25895 fis, Hypothetical protein 863 4831 clone CBR03553Contig34999_RC periplakin Keratinization, Repeat, Coiled coil, 864 4832Cytoskeleton, Structural protein Contig35002_RC FLJ12994 hypotheticalprotein Hypothetical protein 865 4833 FLJ12994 Contig35018_RC zr44a03.s1866 4834 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE: 666220 3′, mRNAsequence. Contig35043 Transcribed 867 4835 sequences Contig35052_RCpituitary tumor- Transmembrane, Nuclear protein 868 4836 transforming 1interacting protein Contig35076_RC Sequence 226 from 869 4837 PatentWO0220754. Contig35094_RC FLJ21478 NOD9 protein Hypothetical protein 8704838 Contig35163_RC Similar to 871 4839 hypothetical protein MG11009.4(LOC285344), mRNA Contig35182_RC qb88b05.x1 872 4840Soares_fetal_heart_NbHH19W Homo sapiens cDNA clone IMAGE: 1707153 3′,mRNA sequence. Contig35187_RC ARL4 ADP-ribosylation GTP-binding,Multigene family, 873 4841 factor-like 4 Nuclear protein Contig35251_RCCDNA: FLJ22719 874 4842 fis, clone HSI14307 Contig35425_RC hypotheticalprotein Hypothetical protein 875 4843 LOC285831 Contig35435_RC FLJ23447hypothetical protein Hypothetical protein 876 4844 FLJ23447Contig35576_RC Transcribed 877 4845 sequences Contig35608_RC df54a02.y1Morton 878 4846 Fetal Cochlea Homo sapiens cDNA clone IMAGE: 2487051 5′,mRNA sequence. Contig35635_RC TAGAP T-cell activation Hypotheticalprotein 879 4847 GTPase activating protein Contig35661_RC DSCR1L2 Downsyndrome Alternative splicing 880 4848 critical region gene 1-like 2Contig35685_RC FLJ13117 spermatogenesis Hypothetical protein 881 4849associated, serine- rich 2 Contig35700_RC CDNA clone 882 4850 IMAGE:6702802, partial cds Contig35713_RC FIS 883 4851 Contig35799_RCcentaurin, beta 2 GTPase activation, Repeat, ANK 884 4852 repeat,Zinc-finger Contig35874_RC Transcribed 885 4853 sequences Contig35896_RCsignal transducer Hypothetical protein, Repeat, WD 886 4854 andactivator of repeat transcription 3 interacting protein 1 Contig35940KIAA1733 RPEL repeat Hypothetical protein 887 4855 containing 1Contig35958_RC MGC13071 hypothetical protein Hypothetical protein,Metal-binding, 888 4856 MGC13071 Nuclear protein, Zinc, Zinc-fingerContig35976_RC family with sequence Signal 889 4857 similarity 3, memberC Contig3597_RC LENG5 leukocyte receptor Receptor, Hypothetical protein890 4858 cluster (LRC) member 5 Contig36020_RC MGC15634 hypotheticalprotein Hypothetical protein 891 4859 MGC15634 Contig36075_RCTranscribed 892 4860 sequences Contig36104_RC CCT6A laa10b09.x1 8 5Chaperone, ATP-binding, Multigene 893 4861 week embryo family anteriortongue 8 5 EAT Homo sapiens cDNA 3′, mRNA sequence. Contig36106_RC NCLhypothetical protein Hypothetical protein 894 4862 LOC157697Contig36125_RC Transcribed 895 4863 sequences Contig36129_RC MGC4707hypothetical protein Hypothetical protein 896 4864 LOC283989Contig3612_RC KIAA1802 chromosome 13 Hypothetical protein,Metal-binding, 897 4865 open reading frame 8 Zinc, Zinc-fingerContig36152_RC sterile alpha motif Hypothetical protein, ANK repeat, 8984866 domain containing 6 Repeat Contig36169_RC DKFZp547E052 hypotheticalprotein Hypothetical protein 899 4867 DKFZp547E052 Contig36178_RCsialyltransferase 9 Transferase, Glycosyltransferase, 900 4868 (CMP-Glycoprotein, Transmembrane, NeuAc:lactosylceramide Signal-anchor, Golgistack alpha-2,3- sialyltransferase; GM3 synthase) Contig36190_RCTranscribed 901 4869 sequences Contig36193_RC inositol 1,4,5- Receptor,Transmembrane, 902 4870 triphosphate Phosphorylation, Ionic channel, Ionreceptor, type 1 transport, Calcium channel Contig36195 Full lengthinsert 903 4871 cDNA clone ZD73D05 Contig3626_RC FLJ13855 hypotheticalprotein Hypothetical protein, Ligase, Ubl 904 4872 FLJ13855 conjugationpathway Contig36323_RC SFXN5 sideroflexin 5 Transport, Iron transport,Iron, 905 4873 Mitochondrion, Transmembrane Contig36359_RC Transcribed906 4874 sequences Contig36369_RC we24d02.x1 907 4875 NCI_CGAP_Lu24 Homosapiens cDNA clone IMAGE: 2342019 3′, mRNA sequence. Contig36409_RCTranscribed 908 4876 sequences Contig36512_RC Transcribed 909 4877sequences Contig36525 ARX aristaless related Homeobox, DNA-binding, 9104878 homeobox Developmental protein, Nuclear protein, Transcriptionregulation, Disease mutation, Triplet repeat expansion, EpilepsyContig36617_RC chromosome 6 open 911 4879 reading frame 182Contig36622_RC Transcribed 912 4880 sequences Contig36628 HANP1 913 4881Contig36634_RC FLJ39514 sec1 family domain Hypothetical protein 914 4882containing 2 Contig36720_RC Transcribed 915 4883 sequencesContig36761_RC FLJ23403 hypothetical protein Hypothetical protein 9164884 FLJ23403 Contig36803_RC FLJ13952 sorting nexin 22 Hypotheticalprotein, Transport, 917 4885 Protein transport Contig36805_RC MGC15435zinc finger, BED Zinc-finger 918 4886 domain containing 3 Contig36810CDNA FLJ37425 fis, 919 4887 clone BRAWH2001530 Contig36876_RC Homosapiens cDNA 920 4888 FLJ32044 fis, clone NTONG2000985. Contig36879_RCClone 921 4889 IMAGE: 4753714, mRNA Contig36888_RC suppression ofHypothetical protein 922 4890 tumorigenicity 7 like Contig36939_RCTranscribed 923 4891 sequences Contig3695_RC MGC17330 HGFL geneHypothetical protein, Glycoprotein, 924 4892 Kringle Contig36973_RCAGMAT Homo sapiens Putrescine biosynthesis, Spermidine 925 4893 cDNA:FLJ23384 fis, biosynthesis, Hydrolase, clone HEP16468. Manganese,Mitochondrion, Transit peptide Contig36976_RC DIBD1 disrupted in bipolarHypothetical protein 926 4894 affective disorder 1 Contig36997_RC biorefzinc finger protein Transcription regulation, DNA- 927 4895 481 binding,Zinc-finger, Metal-binding, Nuclear protein, Repeat Contig37016_RC ING5inhibitor of growth Hypothetical protein 928 4896 family, member 5Contig37025_RC CDNA FLJ41484 fis, 929 4897 clone BRTHA2003030Contig37029_RC FLJ23153 likely ortholog of Hypothetical protein 930 4898mouse tumor necrosis-alpha- induced adipose- related proteinContig37037_RC chromosome 13 931 4899 open reading frame 25Contig37082_RC MGC2408 hypothetical protein Hypothetical protein 9324900 MGC2408 Contig37140_RC membrane protein, Hypothetical protein, SH3domain 933 4901 palmitoylated 7 (MAGUK p55 subfamily member 7)Contig37142_RC Homo sapiens cDNA 934 4902 FLJ12163 fis, cloneMAMMA1000594. Contig37219 MDN1 MDN1, midasin Chaperone, ATP-binding,Repeat, 935 4903 homolog (yeast) Nuclear protein Contig37262 CloneHypothetical protein 936 4904 IMAGE: 5263527, mRNA Contig37300_RCKIAA1904 KIAA1904 protein Hypothetical protein 937 4905 Contig37306_RCMUC16 mucin 16 Hypothetical protein 938 4906 Contig3734_RC RPS8 CloneRibosomal protein 939 4907 IMAGE: 4249217, mRNA Contig37361_RCTranscribed 940 4908 sequences Contig37364_RC Transcribed 941 4909sequences Contig37368_RC nemo like kinase ATP-binding, Kinase, 942 4910Serine/threonine-protein kinase, Transferase Contig37569_RC CDNAFLJ26339 fis, 943 4911 clone HRT02975 Contig37660_RC ADAM6 a disintegrinand 944 4912 metalloproteinase domain 6 Contig37736_RC RAD1 TranscribedHypothetical protein, Ribosome 945 4913 sequence with biogenesis,Nuclear protein, Cell moderate similarity cycle, Exonuclease to proteinref: NP_060312.1 (H. sapiens) hypothetical protein FLJ20489 [Homosapiens] Contig37763_RC Transcribed 946 4914 sequence with moderatesimilarity to protein ref: NP_002945.1 (H. sapiens) ubiquitin andribosomal protein S27a precursor; ubiquitin carboxyl extension protein80; 40S ribosomal protein S27a; ubiquitin; ubiquitin- CEP80 [Homosapiens] Contig37764_RC qa65f01.x1 947 4915 Soares_fetal_heart_NbHH19WHomo sapiens cDNA clone IMAGE: 1691641 3′, mRNA sequence. Contig37895_RCyh88d01.s1 Soares 948 4916 placenta Nb2HP Homo sapiens cDNA clone IMAGE:136801 3′, mRNA sequence. Contig37950_RC qz91d12.x1 949 4917Soares_pregnant_uterus_NbHPU Homo sapiens cDNA clone IMAGE: 2041943 3′,mRNA sequence. Contig37958 KAI1 hypothetical protein Glycoprotein,Transmembrane, 950 4918 LOC284023 Antigen Contig37991_RC LOC133308hypothetical protein Hypothetical protein 951 4919 BC009732Contig38043_RC hypothetical protein 952 4920 LOC199675 Contig38093_RCTranscribed 953 4921 sequences Contig380_RC KIAA1724 selenoprotein I, 1Hypothetical protein, Transferase, 954 4922 Transmembrane, Selenium,Selenocysteine Contig38117_RC Transcribed 955 4923 sequencesContig38155_RC Transcribed 956 4924 sequences Contig38169_RC FLJ13984hypothetical protein Hypothetical protein 957 4925 FLJ13984Contig3820_RC LOC56898 dehydrogenase/reductase Oxidoreductase,Hypothetical protein 958 4926 (SDR family) member 6 Contig38285_RCFLJ10462 male sterility domain Hypothetical protein 959 4927 containing1 Contig38288_RC DKFZp762A2013 quiescin Q6-like 1 Hypothetical protein,Signal 960 4928 Contig382_RC NLI-IF CTD (carboxy- Hypothetical protein,Nuclear protein 961 4929 terminal domain, RNA polymerase II, polypeptideA) small phosphatase 1 Contig38320_RC Transcribed 962 4930 sequencesContig38321_RC Transcribed 963 4931 sequences Contig3834_RC MRNA; cDNA964 4932 DKFZp686K14148 (from clone DKFZp686K14148) Contig38398_RCTranscribed 965 4933 sequences Contig38493_RC CDNA FLJ42010 fis, 9664934 clone SPLEN2032036 Contig38581_RC anaphase promoting Ublconjugation pathway, Cell cycle, 967 4935 complex subunit 1 Celldivision, Mitosis, Repeat Contig38603_RC Transcribed 968 4936 sequencesContig38604_RC CDNA FLJ25042 fis, Hypothetical protein 969 4937 cloneCBL03351 Contig38654_RC solute carrier family 970 4938 28(sodium-coupled nucleoside transporter), member 3 Contig38669_RC HS2ST1heparan sulfate 2-O- Hypothetical protein, Transferase 971 4939sulfotransferase 1 Contig38714_RC Transcribed 972 4940 sequencesContig38721_RC MGC35163 sterile alpha motif Hypothetical protein 9734941 domain containing 3 Contig38724_RC Clone 974 4942 IMAGE: 5275753,mRNA Contig38726_RC SWI/SNF related, Hypothetical protein 975 4943matrix associated, actin dependent regulator of chromatin, subfamily e,member 1 Contig38731_RC frizzled homolog 2 Multigene family, G-proteincoupled 976 4944 (Drosophila) receptor, Transmembrane, Developmentalprotein, Wnt signaling pathway, Glycoprotein, Signal Contig38778 TRIM7tripartite motif- Zinc-finger, Zinc, Coiled coil, Metal- 977 4945containing 7 binding, Polymorphism, Alternative splicing Contig38803_RCRho GTPase GTPase activation, SH3-binding, 3D- 978 4946 activatingprotein 1 structure Contig38877 zv94e09.s1 979 4947 Soares_NhHMPu_S1Homo sapiens cDNA clone IMAGE: 767464 3′, mRNA sequence. Contig38944_RCTranscribed 980 4948 sequences Contig39008_RC MYCL1 v-myc Nuclearprotein, DNA-binding, Proto- 981 4949 myelocytomatosis oncogene viraloncogene homolog 1, lung carcinoma derived (avian) Contig39043_RCzl77f02.s1 982 4950 Stratagene colon (#937204) Homo sapiens cDNA cloneIMAGE: 510651 3′, mRNA sequence. Contig39048_RC TAFA2 proteinHypothetical protein 983 4951 Contig39116_RC a1/3GTP alpha-1,3-Glycosyltransferase, Transferase 984 4952 galactosyltransferasepseudogene Contig3920_RC SP1 Sp1 transcription Hypothetical protein,Transcription 985 4953 factor regulation, Activator, Zinc-finger,Metal-binding, DNA-binding, Nuclear protein, Repeat, Glycoprotein, 3D-structure Contig39236 FLJ00026 Homo sapiens, Hypothetical protein,Guanine- 986 4954 Similar to RIKEN nucleotide releasing factor cDNA5830472H07 gene, clone MGC: 39702 IMAGE: 5271738, mRNA, complete cds.Contig39249 THBS3 thrombospondin 3 Glycoprotein, Cell adhesion, 987 4955Calcium-binding, Repeat, EGF-like domain, Signal Contig39287_RCTranscribed 988 4956 sequence with moderate similarity to protein pir:E54024 (H. sapiens) E54024 protein kinase Contig39297_RC LOC148898hypothetical protein Hypothetical protein 989 4957 BC007899Contig39364_RC UPF3B UPF3 regulator of 990 4958 nonsense transcriptshomolog B (yeast) Contig39403_RC hypothetical protein Hypotheticalprotein 991 4959 FLJ34790 Contig3940_RC C9orf19 chromosome 9 openHypothetical protein 992 4960 reading frame 19 Contig39448_RCN-acetylneuraminate 993 4961 pyruvate lyase (dihydrodipicolinatesynthase) Contig39496_RC FLJ22501 Hermansky-Pudlak Hypothetical protein994 4962 syndrome 6 Contig39545_RC MTIF3 general transcriptionTranscription regulation, Zinc-finger, 995 4963 factor IIIAMetal-binding, DNA-binding, RNA- binding, Repeat, Nuclear protein,Polymorphism Contig39603_RC CNOT3 CCR4-NOT Hypothetical protein 996 4964transcription complex, subunit 3 Contig39626_RC STK35 serine/threonineHypothetical protein, Transferase, 997 4965 kinase 35Serine/threonine-protein kinase, ATP-binding, PhosphorylationContig39702_RC similar to Putative Hypothetical protein 998 4966 proteinC21orf56 Contig39739_RC CDK9 Full length insert Transferase,Serine/threonine- 999 4967 cDNA clone protein kinase, ATP-binding,Nuclear ZA91F08 protein, Polymorphism Contig39797_RC TRIPIN tripinHypothetical protein 1000 4968 Contig39810_RC hypothetical proteinHypothetical protein 1001 4969 MGC43690 Contig39878_RC BOP SET and MYNDTranscription regulation, Repressor, 1002 4970 domain containing 1DNA-binding, Nuclear protein, Zinc- finger, Metal-binding Contig39933_RCLOC90693 Sequence 2 from Hypothetical protein 1003 4971 PatentWO0220754. Contig39989_RC MGC14289 similar to RIKEN 1004 4972 cDNA1200014N16 gene Contig40015_RC Transcribed 1005 4973 sequence withmoderate similarity to protein pdb: 1LBG (E. coli) B Chain B, LactoseOperon Repressor Bound To 21-Base Pair Symmetric Operator Dna, AlphaCarbons Only Contig40026_RC CDNA FLJ12935 fis, 1006 4974 cloneNT2RP2004982 Contig40053_RC HNRPD heterogeneous Nuclear protein,RNA-binding, DNA- 1007 4975 nuclear binding, Ribonucleoprotein, Repeat,ribonucleoprotein D Transcription regulation, Telomere, (AU-rich elementAlternative splicing, 3D-structure RNA binding protein 1, 37 kDa)Contig40055_RC Transcribed 1008 4976 sequences Contig40069_RCTranscribed 1009 4977 sequences Contig40093_RC fatty acid bindingTransport, Lipid-binding, Acetylation, 1010 4978 protein 3, musclePhosphorylation, 3D-structure and heart (mammary-derived growthinhibitor) Contig40094_RC DKFZp434I099 hypothetical protein Hypotheticalprotein 1011 4979 DKFZp434I099 Contig40128_RC hypoxia-inducibleTranscription regulation, Activator, 1012 4980 factor 1, alpha Nuclearprotein, DNA-binding, subunit (basic helix- Alternative splicing,Repeat, loop-helix Acetylation, Hydroxylation, transcription factor)Phosphorylation, S-nitrosylation, Polymorphism, 3D-structure Contig40184SLC2A1 solute carrier family Transmembrane, Sugar transport, 1013 4981 2(facilitated glucose Transport, Glycoprotein, Multigene transporter),family, Disease mutation, 3D- member 1 structure Contig40212_RC CD5 CD5antigen (p56-62) Signal, Transmembrane, 1014 4982 Glycoprotein, T-cell,Repeat Contig40237_RC FLJ12525 hypothetical protein Hypothetical protein1015 4983 FLJ12525 Contig40252_RC CDNA clone Hypothetical protein 10164984 IMAGE: 3462401, partial cds Contig40340_RC hypothetical proteinHypothetical protein 1017 4985 FLJ11000 Contig40389_RC Similar to RIKEN1018 4986 cDNA 3830422K02 (LOC387755), mRNA Contig404 Mesenchymal stem1019 4987 cell protein DSC96 mRNA, partial cds Contig40405_RC MGC10818chromosome 6 open Hypothetical protein 1020 4988 reading frame 148Contig40410 tc14e12.x1 Hypothetical protein 1021 4989 Soares_NhHMPu_S1Homo sapiens cDNA clone IMAGE: 2063854 3′, mRNA sequence. Contig40450_RCTHAP domain Hypothetical protein 1022 4990 containing 9 Contig40552_RCFLJ25348 hypothetical protein Hypothetical protein 1023 4991 FLJ25348Contig40651_RC Transcribed 1024 4992 sequences Contig40676_RC Sequence60 from 1025 4993 Patent WO0220754. Contig40830_RC TSGA14 testisspecific, 14 Hypothetical protein 1026 4994 Contig40832_RC Transcribed1027 4995 sequences Contig40897_RC DKFZP434J037 likely ortholog of ratHypothetical protein, ATP-binding, 1028 4996 SNF1/AMP-activated Kinase,Serine/threonine-protein protein kinase kinase, TransferaseContig40960_RC FLJ36991 zinc finger protein Hypothetical protein,Metal-binding, 1029 4997 565 Nuclear protein, Zinc, Zinc-fingerContig40965_RC MGC4504 hypothetical protein Hypothetical protein 10304998 MGC4504 Contig40967_RC LOC389388 1031 4999 (LOC389388), mRNAContig41005_RC Transcribed 1032 5000 sequence with strong similarity toprotein pdb: 1BGM (E. coli) O Chain O, Beta-Galactosidase Contig41035golgi phosphoprotein 4 1033 5001 Contig41041_RC CDNA FLJ32274 fis, 10345002 clone PROST2000036 Contig41080_RC Transcribed 1035 5003 sequencesContig41086_RC forkhead box P1 Hypothetical protein, Transcription 10365004 regulation, DNA-binding, Zinc-finger, Metal-binding, Nuclearprotein, Alternative splicing Contig41094_RC EDG8 endothelialHypothetical protein, Receptor 1037 5005 differentiation, sphingolipidG- protein-coupled receptor, 8 Contig41121_RC FCRH3 Fc receptor-likeImmunoglobulin domain, Receptor 1038 5006 protein 3 Contig41209_RCFLJ21432 adiponectin receptor 2 Fatty acid metabolism, Lipid 1039 5007metabolism, Receptor, Transmembrane Contig41226_RC MRNA; cDNAHypothetical protein 1040 5008 DKFZp434O232 (from clone DKFZp434O232)Contig412_RC FLJ22233 Homo sapiens cDNA Hypothetical protein 1041 5009FLJ36755 fis, clone UTERU2018180, weakly similar to Na+/Ca2+,K+-exchanging protein homolog C13D9.8. Contig41301 LOC152217 hypotheticalprotein Hypothetical protein 1042 5010 BC007882 Contig41421_RC FLJ36156piwi-like 2 Hypothetical protein 1043 5011 (Drosophila) Contig41448_RCdynamin 1-like 1044 5012 Contig41537 MGC20496 methylmalonic Transferase,Mitochondrion, Transit 1045 5013 aciduria (cobalamin peptide,Polymorphism, Disease deficiency) type B mutation Contig41560_RC CPT1Acarnitine Transferase, Acyltransferase, 1046 5014 palmitoyltransferaseMitochondrion, Outer membrane, 1A (liver) Fatty acid metabolism,Transport, Transmembrane, Multigene family Contig41612_RC hypotheticalprotein Hypothetical protein 1047 5015 LOC132241 Contig41618_RC CloneHypothetical protein 1048 5016 IMAGE: 5315196, mRNA Contig41638_RCSLC26A8 solute carrier family 1049 5017 26, member 8 Contig41656_RCSimilar to Eph 1050 5018 receptor A7, clone IMAGE: 5273054, mRNAContig41701_RC Transcribed 1051 5019 sequences Contig41748_RC ELMO3engulfment and cell Apoptosis, Phagocytosis, 1052 5020 motility 3(ced-12 Cytoskeleton, Membrane, SH3- homolog, C. elegans) bindingContig41774_RC Transcribed 1053 5021 sequences Contig41781_RC ARHGEF7Rho guanine Guanine-nucleotide releasing factor, 1054 5022 nucleotideexchange SH3 domain, Alternative splicing, factor (GEF) 7 3D-structure,Hypothetical protein Contig41828_RC Clone 1055 5023 IMAGE: 5310874, mRNAContig41864_RC ZFP106 zinc finger protein Hypothetical protein,Metal-binding, 1056 5024 106 homolog Repeat, WD repeat, Zinc,Zinc-finger (mouse) Contig41869_RC SFRS3 splicing factor, Nuclearprotein, RNA-binding, 1057 5025 arginine/serine-rich 3 mRNA splicing,Alternative splicing, Phosphorylation, Repeat Contig41903_RC FLJ21657hypothetical protein Hypothetical protein 1058 5026 FLJ21657Contig41923_RC OATL1 ornithine Transferase, Aminotransferase 1059 5027aminotransferase- like 1 Contig41936_RC MSL3L1 male-specific lethalChromatin regulator, Nuclear 1060 5028 3-like 1 (Drosophila) protein,Transcription regulation, Alternative splicing Contig41983_RC ym35b12.s1Soares 1061 5029 infant brain 1NIB Homo sapiens cDNA clone IMAGE: 501443′, mRNA sequence. Contig42005_RC splicing factor, Nuclear protein,RNA-binding, 1062 5030 arginine/serine-rich mRNA splicing, Repeat 11Contig42006_RC RasGEF domain Hypothetical protein 1063 5031 family,member 1B Contig42012_RC zinc finger, DHHC Transmembrane, Zinc-finger1064 5032 domain containing 21 Contig42014_RC RNTRE USP6 N-terminal likeHypothetical protein 1065 5033 Contig42076_RC FLJ39091 zinc bindingalcohol Hypothetical protein 1066 5034 dehydrogenase, domain containing1 Contig42105_RC MRNA; cDNA 1067 5035 DKFZp686P24244 (from cloneDKFZp686P24244) Contig42146_RC chromosome 19 Hypothetical protein 10685036 open reading frame 12 Contig42154_RC FLJ11795 hypothetical proteinHypothetical protein 1069 5037 FLJ11795 Contig42174 FLJ33215hypothetical protein Hypothetical protein 1070 5038 FLJ33215Contig42177_RC zinc finger, DHHC Hypothetical protein, 1071 5039 domaincontaining Transmembrane, Zinc-finger 19 Contig42185_RC TLR8 toll-likereceptor 8 Hypothetical protein, Receptor, 1072 5040 Immune response,Inflammatory response, Signal, Transmembrane, Repeat, Leucine-richrepeat, Glycoprotein Contig421_RC KIAA1821 rab11-family Hypotheticalprotein 1073 5041 interacting protein 4 Contig42256_RC Transcribed 10745042 sequences Contig42263_RC PSMB5 ATP synthase, H+ Hydrogen iontransport, CF(0), 1075 5043 transporting, Mitochondrion, Transitpeptide, mitochondrial F0 Hypothetical protein complex, subunit s(factor B) Contig42270_RC similar to metallo- Hypothetical protein 10765044 beta-lactamase superfamily protein Contig42330_RC Transcribed 10775045 sequences Contig42342_RC CDNA FLJ39417 fis, Hypothetical protein1078 5046 clone PLACE6016942 Contig42418_RC Transcribed 1079 5047sequence with weak similarity to protein ref: NP_060265.1 (H. sapiens)hypothetical protein FLJ20378 [Homo sapiens] Contig42437_RC C1orf28casein kinase 1, Transferase, Serine/threonine- 1080 5048 epsilonprotein kinase, ATP-binding, Phosphorylation, Multigene familyContig42459_RC FLJ22021 hypothetical protein Repeat, WD repeat 1081 5049FLJ22021 Contig42566_RC FLJ14761 hypothetical protein Hypotheticalprotein 1082 5050 FLJ14761 Contig42591_RC shadow of prion 1083 5051protein Contig42593_RC Transcribed 1084 5052 sequences Contig42597_RCwd88a09.x1 1085 5053 NCI_CGAP_Lu24 Homo sapiens cDNA clone IMAGE:2338648 3′, mRNA sequence. Contig42615_RC AMID apoptosis-inducingHypothetical protein 1086 5054 factor (AIF)- homologous mitochondrion-associated inducer of death Contig42617_RC SNRPG Human S6 H-8 Ubiquitinconjugation, Hydrolase, 1087 5055 mRNA expressed in Thiol protease,Multigene family, chromosome 6- Alternative splicing suppressed melanomacells. Contig42666_RC chromosome 10 Hypothetical protein 1088 5056 openreading frame 47 Contig42759_RC BCL11B B-cell B-cell, Metal-binding,Zinc, Zinc- 1089 5057 CLL/lymphoma 11B finger (zinc finger protein)Contig42787_RC hypothetical protein Hypothetical protein 1090 5058MGC5509 Contig42824_RC FLJ10785 ubiquitin specific Ubl conjugationpathway, Hydrolase, 1091 5059 protease 40 Thiol protease, Alternativesplicing, Polymorphism, Multigene family Contig42854 CDNA FLJ33578 fis,1092 5060 clone BRAMY2011639 Contig42903_RC Transcribed 1093 5061sequence with strong similarity to protein ref: NP_002745.1 (H. sapiens)mitogen-activated protein kinase 13; mitogen-activated protein kinasep38 delta; stress- activated protein kianse 4 [Homo sapiens]Contig42959_RC solute carrier family Hypothetical protein 1094 5062 5(sodium/glucose cotransporter), member 10 Contig42962_RC Transcribed1095 5063 sequence with weak similarity to protein pir: S41161 (H.sapiens) S41161 keratin 9, cytoskeletal - human Contig43022_RC similarto RIKEN 1096 5064 cDNA 2610524G09 Contig43026_RC hypothetical proteinHypothetical protein 1097 5065 DKFZp762C1112 Contig43096_RC Clone 10985066 IMAGE: 5743799, mRNA Contig43169_RC DEAD (Asp-Glu-Ala- ATP-binding,Helicase, Hydrolase, 1099 5067 Asp) box polypeptide Hypothetical protein51 Contig43184_RC yg20d12.s1 Soares 1100 5068 infant brain 1NIB Homosapiens cDNA clone IMAGE: 329183′, mRNA sequence. Contig43189_RCTranscribed 1101 5069 sequences Contig43241_RC ADCY7 adenylate cyclase 7Lyase, cAMP biosynthesis, 1102 5070 Transmembrane, Glycoprotein, Repeat,Metal-binding, Magnesium Contig43253_RC KIAA1858 zinc finger proteinTranscription regulation, DNA- 1103 5071 469 binding, Zinc-finger,Metal-binding, Nuclear protein, Repeat Contig43262_RC Transcribed 11045072 sequences Contig43277_RC Similar to KIAA1726 1105 5073 protein(LOC340554), mRNA Contig43289_RC hypothetical protein 1106 5074LOC170371 Contig43385_RC DKFZp762O076 hypothetical protein Hypotheticalprotein 1107 5075 DKFZp762O076 Contig43436_RC FLJ32028 hypotheticalprotein Hypothetical protein 1108 5076 FLJ32028 Contig43486_RC DRB1developmentally Hypothetical protein 1109 5077 regulated RNA- bindingprotein 1 Contig43506_RC GLI pathogenesis- 1110 5078 related 1 (glioma)Contig43513_RC TIGD7 Homo sapiens cDNA 1111 5079 FLJ13533 fis, clonePLACE1006371. Contig43534 ankyrin repeat Hypothetical protein, ANKrepeat, 1112 5080 domain 10 Repeat Contig43540_RC GRIM19 FLJ44968protein Oxidoreductase, Ubiquinone, NAD, 1113 5081 Apoptosis,Mitochondrion, Transmembrane, Acetylation, Hypothetical proteinContig43542_RC KIAA1718 protein Hypothetical protein 1114 5082Contig43549_RC SNX5 Homo sapiens, clone Hypothetical protein, Transport,1115 5083 MGC: 3411 Protein transport IMAGE: 3629947, mRNA, completecds. Contig43586_RC hypothetical protein 1116 5084 LOC134218Contig43645_RC hypothetical protein Hypothetical protein 1117 5085LOC129607 Contig43655_RC NAG14 leucine rich repeat Immunoglobulindomain, 1118 5086 containing 4 Hypothetical protein, SignalContig43658_RC likely ortholog of 1119 5087 mouse cancer related gene -liver 2 Contig4365_RC TGOLN2 trans-golgi network Hypothetical protein,Signal, 1120 5088 protein 2 Transmembrane, Glycoprotein, Repeat, Golgistack, Alternative splicing Contig43673_RC FLJ20481 calpain smallsubunit 2 Hypothetical protein 1121 5089 Contig43679_RC MEF-2 myelinexpression Hypothetical protein 1122 5090 factor 2 Contig43694_RCTSPAN-2 tetraspan 2 Glycoprotein, Transmembrane 1123 5091 Contig43703_RCCDH13 CDNA FLJ25967 fis, Cell adhesion, Glycoprotein, 1124 5092 cloneCBR01929 Calcium-binding, Repeat, GPI- anchor, Signal Contig43724_RCFLJ13213 hypothetical protein Hypothetical protein 1125 5093 FLJ13213Contig43746_RC CDNA FLJ41107 fis, 1126 5094 clone BLADE2007923Contig43749_RC MGC14258 Rho GTPase Hypothetical protein 1127 5095activating protein 19 Contig43750_RC cleavage and 1128 5096polyadenylation specific factor 6, 68 kDa Contig43817_RC RINZF zincfinger and BTB Hypothetical protein, Metal-binding, 1129 5097 domaincontaining Zinc, Zinc-finger 10 Contig438_RC hypothetical proteinEGF-like domain, Hypothetical 1130 5098 MGC61716 protein Contig4399_RCMYH9 myosin, heavy Myosin, ATP-binding, Calmodulin- 1131 5099polypeptide 9, non- binding, Actin-binding, Coiled coil, muscleMultigene family, Disease mutation, Deafness, Hypothetical proteinContig440 MGC3165 Homo sapiens, H2A Acetylation, Chromosomal 1132 5100histone family, protein, DNA-binding, Multigene member L, clone family,Nuclear protein, Nucleosome MGC: 3165 core IMAGE: 3355200, mRNA,complete cds. Contig44059_RC hypothetical protein Hypothetical protein1133 5101 DKFZp564B1162 Contig44078 TA-WDRP T-cell activation WDHypothetical protein, Repeat, WD 1134 5102 repeat protein repeatContig44105 OSBPL11 oxysterol binding Hypothetical protein, Lipidtransport, 1135 5103 protein-like 11 Transport Contig44124_RC CDNAFLJ30906 fis, Hypothetical protein 1136 5104 clone FEBRA2006055Contig44133_RC FLJ11362 hypothetical protein Hypothetical protein, ANKrepeat, 1137 5105 FLJ11362 Repeat Contig44192_RC Cas-Br-M (murine)Hypothetical protein, Ligase, Ubl 1138 5106 ecotropic retroviralconjugation pathway, Proto- transforming oncogene, Zinc-finger, SH2domain, sequence Phosphorylation, Calcium-binding, 3D-structureContig44226_RC TIGD2 tigger transposable 1139 5107 element derived 2Contig44265_RC ATPase, Hydrolase, Transmembrane, 1140 5108aminophospholipid Phosphorylation, Magnesium, ATP- transporter (APLT),binding, Alternative splicing, Class I, type 8A, Multigene family member1 Contig44278_RC DKFZp434K114 WD repeat domain Repeat, WD repeat,Hypothetical 1141 5109 21 protein, Plasmid Contig44343 CDNA FLJ26676fis, 1142 5110 clone MPG03726 Contig44358_RC DKFZp434N035 HypotheticalHypothetical protein 1143 5111 LOC284874 (LOC284874), mRNA Contig44409similar to LL5 beta Hypothetical protein 1144 5112 Contig44414_RCSLC30A1 solute carrier family Zinc transport, Transport, 1145 5113 30(zinc transporter), Transmembrane, Multigene family member 1Contig44492_RC Transcribed 1146 5114 sequences Contig44518_RC FAM11Afamily with sequence Antigen, Multigene family, Tumor 1147 5115similarity 11, antigen, Hypothetical protein member A Contig44521_RCLSM8 homolog, U6 Nuclear protein, Ribonucleoprotein, 1148 5116 smallnuclear RNA mRNA splicing, mRNA processing, associated (S. cerevisiae)RNA-binding, Acetylation Contig44548_RC hypothetical protein 1149 5117LOC283508 Contig44593_RC retinoblastoma Hypothetical protein,Metal-binding, 1150 5118 binding protein 6 Zinc, Zinc-fingerContig44595_RC hypothetical protein Hypothetical protein 1151 5119MGC45840 Contig44596_RC PPIL3 peptidylprolyl Isomerase, Rotamase,Hypothetical 1152 5120 isomerase protein (cyclophilin)-like 3Contig44708_RC BCAT1 Homo sapiens Hypothetical protein, Transferase,1153 5121 cDNA: FLJ21270 fis, Aminotransferase, Branched-chain cloneCOL01749. amino acid biosynthesis, Pyridoxal phosphate Contig44713transducin-like Transcription regulation, Repressor, 1154 5122 enhancerof split 4 Nuclear protein, Repeat, WD repeat, (E(sp1) homolog,Phosphorylation, Wnt signaling Drosophila) pathway Contig44720_RC FKSG32hypothetical protein Hypothetical protein 1155 5123 FKSG32Contig44723_RC Human cAMP- 1156 5124 binding guanine nucleotide exchangefactor IV (cAMP- GEFIV) mRNA, clone W15, partial sequence Contig44757_RCVIM Transcribed Hypothetical protein, Coiled coil, 1157 5125 sequencewith Intermediate filament, strong similarity to Phosphorylation,3D-structure protein pir: A25074 (H. sapiens) A25074 vimentin - humanContig44817_RC C20orf147 chromosome 20 Hydrolase 1158 5126 open readingframe 147 Contig44874_RC LOC57805 p30 DBC protein Hypothetical protein1159 5127 Contig44877_RC KIAA1877 beta-galactoside Hypothetical protein,Transferase, 1160 5128 alpha-2,6- Glycosyltransferase sialyltransferaseII Contig44964_RC hypothetical gene 1161 5129 supported by BC017510;BC046919 Contig45004_RC hypothetical protein 1162 5130 LOC283129Contig45080_RC CUL5 cullin 5 Ubl conjugation pathway, Ubl 1163 5131conjugation, Receptor Contig45085_RC ATP6V0A2 Homo sapiens cDNA Hydrogenion transport, 1164 5132 FLJ32238 fis, clone Transmembrane,Glycoprotein, PLACE6004993. Hypothetical protein Contig45135 CDNA:FLJ22382 1165 5133 fis, clone HRC07514 Contig45201_RC C1QTNF2 C1q andtumor Collagen, Signal 1166 5134 necrosis factor related protein 2Contig45290_RC Similar to RIKEN 1167 5135 cDNA 3010021M21 (LOC388185),mRNA Contig45304_RC DEPC-1 prostate cancer 1168 5136 antigen-1Contig45305_RC MGC3130 hypothetical protein Hypothetical protein 11695137 MGC3130 Contig45328_RC Similar to Ab2-183 1170 5138 (LOC158830),mRNA Contig45338_RC CSNK2A1 casein kinase 2, Transferase,Serine/threonine- 1171 5139 alpha 1 polypeptide protein kinase,ATP-binding, Wnt signaling pathway, 3D-structure Contig45377_RC C10orf2progressive external Hypothetical protein, Helicase 1172 5140ophthalmoplegia 1 Contig45381_RC hypothetical protein 1173 5141LOC283663 Contig45396_RC FLJ13197 hypothetical protein Hypotheticalprotein 1174 5142 FLJ13197 Contig45397_RC FLJ34299 zinc finger protein92 Hypothetical protein, Metal-binding, 1175 5143 (HTF12) Nuclearprotein, Zinc, Zinc-finger, Transcription regulation, DNA- binding,Repeat Contig45437 similar to RNA Hypothetical protein 1176 5144polymerase B transcription factor 3 Contig45440_RC Similar to RIKEN 11775145 cDNA 9330196J05 (LOC340075), mRNA Contig45455_RC soluble liver 11785146 antigen/liver pancreas antigen Contig45457_RC CYP4F12 cytochromeP450, Oxidoreductase, Monooxygenase, 1179 5147 family 4, subfamilyElectron transport, Membrane, F, polypeptide 12 Heme, Microsome,Endoplasmic reticulum, Polymorphism Contig45540_RC G protein-coupledReceptor 1180 5148 receptor 114 Contig45544_RC protein kinase,Hypothetical protein, Kinase 1181 5149 interferon-inducible doublestranded RNA dependent activator Contig45569_RC CDC14B CDC14 celldivision Hydrolase 1182 5150 cycle 14 homolog B (S. cerevisiae)Contig45624_RC HAKAI Cas-Br-M (murine) Hypothetical protein,Metal-binding, 1183 5151 ecotropic retroviral Zinc, Zinc-fingertransforming sequence-like 1 Contig45634_RC Similar to FLJ46354Hypothetical protein 1184 5152 protein (LOC389694), mRNA Contig45642_RCmitogen-activated ATP-binding, Kinase, Transferase, 1185 5153 proteinkinase Serine/threonine-protein kinase, kinase kinase 2 Hypotheticalprotein Contig45790_RC KIAA0187 ESTs, Moderately 1186 5154 similar toKIAA0187 gene product [Homo sapiens] [H. sapiens] Contig45800_RC MTX1metaxin 1 Mitochondrion, Outer membrane, 1187 5155 Transmembrane,Transport, Protein transport Contig45816_RC MGC4832 chromosome 13Hypothetical protein 1188 5156 open reading frame 3 Contig45821_RC ADCY4adenylate cyclase 4 Hypothetical protein, Lyase, cAMP 1189 5157biosynthesis, Transmembrane, Glycoprotein, Repeat, Metal-binding,Magnesium Contig45847_RC DKFZP761I2123 hypothetical protein Hypotheticalprotein 1190 5158 DKFZp761I2123 Contig45879_RC KIAA1145 KIAA1145 proteinHypothetical protein, 1191 5159 Transmembrane Contig45891_RC CDNAFLJ37509 fis, 1192 5160 clone BRCAN1000065 Contig45944_RC ZNF335 zincfinger protein Transcription regulation, Zinc-finger, 1193 5161 335Metal-binding, Nuclear protein, DNA- binding, Repeat Contig45945_RCTranscribed 1194 5162 sequences Contig4595 hypothetical Hypotheticalprotein 1195 5163 LOC387763 Contig45975_RC Transcribed 1196 5164sequences Contig45984 USP7 ubiquitin specific Ubl conjugation pathway,Hydrolase, 1197 5165 protease 7 (herpes Thiol protease, Multigenefamily, virus-associated) Nuclear protein, 3D-structure Contig46052_RCectonucleoside Hydrolase, Transmembrane, 1198 5166 triphosphate Antigen,Glycoprotein, Calcium, diphosphohydrolase 1 Magnesium, Alternativesplicing, Lipoprotein, Palmitate Contig46178_RC Homo sapiens, clone 11995167 IMAGE: 5276307, mRNA. Contig461_RC KIAA1836 KIAA1836 proteinHypothetical protein 1200 5168 Contig46202 MAD MAX dimerization Nuclearprotein, DNA-binding, 1201 5169 protein 1 Transcription regulation,Repressor, 3D-structure Contig46218_RC Similar to 1202 5170 diaphanoushomolog 3 (Drosophila), clone IMAGE: 5277415, mRNA Contig46244_RC Clone1203 5171 IMAGE: 111705 mRNA sequence Contig46262_RC Similar to 12045172 2010300C02Rik protein (LOC343990), mRNA Contig46265_RC LOH11CR1Jgene, 1205 5173 loss of heterozygosity, 11, chromosomal region 1 gene Jproduct Contig46294_RC Transcribed 1206 5174 sequence with weaksimilarity to protein ref: NP_060312.1 (H. sapiens) hypothetical proteinFLJ20489 [Homo sapiens] Contig46306_RC CDNA FLJ36097 fis, 1207 5175clone TESTI2020956 Contig46343_RC SPP1 suppressor of SH2 domain, Growthregulation, 1208 5176 cytokine signaling 7 Signal transduction inhibitorContig46375_RC CDNA FLJ26349 fis, 1209 5177 clone HRT04618Contig46376_RC zinc finger and BTB Hypothetical protein, Metal-binding,1210 5178 domain containing Zinc, Zinc-finger 10 Contig46399_RCTranscribed 1211 5179 sequences Contig46416_RC MGC33212 hypotheticalprotein 1212 5180 MGC33212 Contig46421_RC Transcribed 1213 5181 sequencewith moderate similarity to protein ref: NP_005496.1 (H. sapiens) CD36antigen Contig46437_RC synaptotagmin Transport, Protein transport 12145182 binding, cytoplasmic RNA interacting protein Contig46443_RC solutecarrier family Hypothetical protein 1215 5183 26, member 11Contig46464_RC Transcribed 1216 5184 sequences Contig46482_RC MRNA; cDNA1217 5185 DKFZp434C1435 (from clone DKFZp434C1435) Contig46506_RC MRNA;cDNA 1218 5186 DKFZp686C18110 (from clone DKFZp686C18110) Contig46536_RCLGI3 leucine-rich repeat Repeat, Leucine-rich repeat, Signal, 1219 5187LGI family, member 3 Hypothetical protein Contig46563_RC Transcribed1220 5188 sequences Contig46567 Transcribed 1221 5189 sequencesContig46586 UBE2D3 ubiquitin-conjugating Hypothetical protein, Ligase,Ubl 1222 5190 enzyme E2D 3 conjugation pathway, Multigene (UBC4/5homolog, family yeast) Contig46590 RAD50 CDNA FLJ46914 fis, Hypotheticalprotein 1223 5191 clone SPLEN2027852 Contig46591_RC hypothetical protein1224 5192 LOC90639 Contig46601_RC CDNA FLJ42198 fis, 1225 5193 cloneTHYMU2034338 Contig46602_RC zinc finger, CCHC Hypothetical protein 12265194 domain containing 6 Contig46634 Transcribed 1227 5195 sequencesContig46700_RC LSP1 small proline rich Phosphorylation, T-cell 1228 5196protein 4 Contig46709_RC FLJ23045 chromosome 20 Transport, Proteintransport, 1229 5197 open reading frame Hypothetical protein 23Contig46732_RC zinc finger protein Hypothetical protein, Zinc-finger,1230 5198 207 Metal-binding, DNA-binding, Nuclear protein, Alternativesplicing Contig46747_RC parvin, gamma Cell adhesion, Cytoskeleton,Actin- 1231 5199 binding, Repeat, Alternative splicing Contig46860_RCFLJ20758 protein Hypothetical protein 1232 5200 Contig46881_RCTranscribed 1233 5201 sequences Contig46954_RC PNMA3 paraneoplasticHypothetical protein 1234 5202 antigen MA3 Contig46999_RC CDNA FLJ26950fis, 1235 5203 clone RCT08544 Contig47014_RC MGC24180 hypotheticalprotein Hypothetical protein 1236 5204 MGC24180 Contig47015_RChypothetical protein Hypothetical protein 1237 5205 FLJ21439Contig47025_RC Hypothetical gene 1238 5206 supported by AK094796(LOC400764), mRNA Contig47042 FLJ20069 Abelson helper Hypotheticalprotein, Repeat, SH3 1239 5207 integration site domain, WD repeatContig47081_RC LOC392751 1240 5208 (LOC392751), mRNA Contig47096_RCPFKFB4 6-phosphofructo-2- Multifunctional enzyme, Transferase, 1241 5209kinase/fructose-2,6- Kinase, Hydrolase, ATP-binding, biphosphatase 4Phosphorylation, Multigene family, 3D-structure Contig47184_RC LOC4008131242 5210 (LOC400813), mRNA Contig47203_RC sortilin-related Endocytosis,Receptor, 1243 5211 receptor, L(DLR Transmembrane, EGF-like domain,class) A repeats- Repeat, Glycoprotein, LDL, Lipid containing transport,Cholesterol metabolism, Signal Contig47221_RC VCP valosin-containingATP-binding, Transport, 1244 5212 protein Phosphorylation, Repeat, Golgistack, Endoplasmic reticulum, Hypothetical protein Contig47368_RCLOC92691 hypothetical protein Hypothetical protein 1245 5213 BC008604Contig47441_RC ubiquitin-conjugating Ligase, Ubl conjugation pathway,1246 5214 enzyme E2 variant 2 Vitamin D Contig47464_RC ZNF335 zincfinger protein Transcription regulation, Zinc-finger, 1247 5215 335Metal-binding, Nuclear protein, DNA- binding, Repeat Contig47495_RC IDI2GTP binding protein 4 GTP-binding, Nuclear protein 1248 5216Contig47498_RC TMPRSS5 transmembrane Hydrolase, Serine protease, 12495217 protease, serine 5 Transmembrane, Signal-anchor, (spinesin)Glycoprotein Contig47539_RC SGT1, suppressor of Ubl conjugation pathway,Repeat, 1250 5218 G2 allele of SKP1 TPR repeat (S. cerevisiae)Contig47582_RC FLJ22757 family with sequence Hypothetical protein 12515219 similarity 31, member C Contig47732_RC EPS8R3 EPS8-like 3 SH3domain, Hypothetical protein, 1252 5220 Receptor Contig47770_RC LY6G6Clymphocyte antigen Signal 1253 5221 6 complex, locus G6C Contig47793_RCFLJ23311 FLJ23311 protein Hypothetical protein 1254 5222 Contig47801_RCCDNA FLJ45814 fis, 1255 5223 clone NT2RP7018126 Contig47810_RC IMMP2LIMP2 inner Coated pits 1256 5224 mitochondrial membrane protease- like(S. cerevisiae) Contig47814_RC HHGP phosphoribosyl Transferase 1257 5225transferase domain containing 1 Contig47835_RC similar to RIKENHypothetical protein 1258 5226 cDNA 2600017H02 Contig47863_RC FLJ11939latrophilin 1 Hypothetical protein, Receptor, 1259 5227 TransmembraneContig47889_RC COPS7B COP9 constitutive Hypothetical protein 1260 5228photomorphogenic homolog subunit 7B (Arabidopsis) Contig47900_RCFLJ12604 hypothetical protein Hypothetical protein 1261 5229 FLJ12604Contig47912_RC NR1D2 nuclear receptor Hypothetical protein, Receptor,1262 5230 subfamily 1, group Transcription regulation, DNA- D, member 2binding, Nuclear protein, Zinc-finger, Repressor Contig47922_RC BRAPBRCA1 associated Metal-binding, Zinc, Zinc-finger 1263 5231 proteinContig47926_RC FLJ13057 germ cell-less Hypothetical protein 1264 5232homolog 1 (Drosophila) Contig47942_RC LOC91893 hypothetical proteinHypothetical protein 1265 5233 BC006136 Contig47975_RC CDNA clone 12665234 IMAGE: 5757380, partial cds Contig47982_RC hypothetical protein1267 5235 LOC112868 Contig48059 FLJ12788 hypothetical proteinHypothetical protein 1268 5236 FLJ12788 Contig48144_RC FLJ11152chromosome 6 open Hypothetical protein 1269 5237 reading frame 70Contig48156_RC proprotein Cholesterol metabolism, Lipid 1270 5238convertase metabolism, Hydrolase, Protease, subtilisin/kexin type 9Serine protease, Calcium, Signal, Autocatalytic cleavage, Zymogen,Glycoprotein, Alternative splicing, Polymorphism, Disease mutationContig48168_RC LOC113246 CDNA FLJ46484 fis, Hypothetical protein 12715239 clone THYMU3026350 Contig48215_RC FLJ35801 hypothetical proteinHypothetical protein 1272 5240 FLJ35801 Contig48249_RC FLJ10849hypothetical protein Hypothetical protein 1273 5241 FLJ10849Contig48270_RC LOC144097 hypothetical protein Hypothetical protein 12745242 BC007540 Contig48277_RC FLJ36175 hypothetical protein Repeat, WDrepeat, Hypothetical 1275 5243 FLJ36175 protein Contig48290_RC MN7 CDNAFLJ43285 fis, Hypothetical protein 1276 5244 clone MESAN2000067Contig48355_RC methionine 1277 5245 aminopeptidase 1D Contig48371 malateOxidoreductase, Tricarboxylic acid 1278 5246 dehydrogenase 1, cycle, NADNAD (soluble) Contig48406_RC chromosome 12 Hypothetical protein 12795247 open reading frame 6 Contig48466_RC FLJ12649 hypothetical proteinHypothetical protein 1280 5248 FLJ12649 Contig48472_RC MAD3 MAXdimerization Hypothetical protein 1281 5249 protein 3 Contig48480_RCring finger protein 24 Zinc-finger 1282 5250 Contig48489_RC similar toHypothetical protein 1283 5251 K06A9.1b.p Contig48506_RC KIAA1799KIAA1799 protein Hypothetical protein 1284 5252 Contig48529_RC CKLFSF2chemokine-like Chemotaxis, Cytokine, 1285 5253 factor super family 2Transmembrane Contig48588_RC KIAA1706 KIAA1706 protein Hypotheticalprotein 1286 5254 Contig48697_RC PFKFB2 6-phosphofructo-2-Multifunctional enzyme, Transferase, 1287 5255 kinase/fructose-2,6-Kinase, Hydrolase, ATP-binding, biphosphatase 2 Phosphorylation,Alternative splicing, Multigene family Contig48722_RC Clone 1288 5256IMAGE: 5729395, mRNA Contig48764_RC CDNA clone Hypothetical protein 12895257 MGC: 71984 IMAGE: 4280819, complete cds Contig48806_RC Similar toRIKEN 1290 5258 cDNA E130012A19 (LOC390789), mRNA Contig48830_RC RPL13ribosomal protein Ribosomal protein 1291 5259 L13 Contig48834_RC YR-29KIAA0888 protein Nuclear protein 1292 5260 Contig48914_RC hypotheticalprotein Hypothetical protein 1293 5261 MGC24133 Contig48944_RCTranscribed 1294 5262 sequences Contig48951_RC chromosome 9 openHypothetical protein 1295 5263 reading frame 85 Contig48983_RC CDNAFLJ14294 fis, 1296 5264 clone PLACE1008181 Contig48988_RC LOC51099abhydrolase domain Hypothetical protein 1297 5265 containing 5Contig49000_RC CDNA FLJ30257 fis, 1298 5266 clone BRACE2002467Contig49012_RC hypothetical protein Hypothetical protein 1299 5267DKFZp434J0617 Contig49063_RC A1BG alpha-1-B Hypothetical protein, 13005268 glycoprotein Immunoglobulin domain, Glycoprotein, Plasma, Repeat,Signal Contig49169_RC SUV39H2 suppressor of Hypothetical protein,Transferase, 1301 5269 variegation 3-9 Methyltransferase, Chromatinhomolog 2 regulator, Nuclear protein, (Drosophila) Alternative splicingContig49185_RC MGC2744 hypothetical protein Hypothetical protein 13025270 MGC2744 Contig49233_RC NRBF-2 nuclear receptor Receptor,Hypothetical protein 1303 5271 binding factor 2 Contig49254_RC RAD53Homo sapiens, clone Hypothetical protein, ATP-binding, 1304 5272 MGC:2637 Kinase, Serine/threonine-protein IMAGE: 3505128, kinase,Transferase, Cell cycle, mRNA, complete Phosphorylation, Nuclearprotein, cds. Disease mutation, Li-Fraumeni syndrome, 3D-structureContig49255_RC leucine-rich PPR- Hypothetical protein, Repeat 1305 5273motif containing Contig49279_RC hypothetical protein Hypotheticalprotein 1306 5274 FLJ25461 Contig49306_RC DKFZP586K0717 ligand of numb-Zinc-finger, Repeat, Alternative 1307 5275 protein X splicingContig49344 FLJ22474 growth hormone Hypothetical protein 1308 5276regulated TBC protein 1 Contig49353_RC MGC41917 zinc finger proteinHypothetical protein, Metal-binding, 1309 5277 550 Nuclear protein,Zinc, Zinc-finger Contig49409 ty82g05.x1 1310 5278 NCI_CGAP_Kid11 Homosapiens cDNA clone IMAGE: 2285624 3′, mRNA sequence. Contig49468_RCMRNA; cDNA 1311 5279 DKFZp667N1113 (from clone DKFZp667N1113)Contig49509_RC KIAA1673 cytoplasmic Hypothetical protein 1312 5280polyadenylation element binding protein 4 Contig49522_RC hypotheticalprotein Hypothetical protein 1313 5281 FLJ13105 Contig49578_RC FLJ20274xj92d05.x1 Hypothetical protein 1314 5282 Soares_NFL_T_GBC_S1 Homosapiens cDNA clone IMAGE: 2664681 3′, mRNA sequence. Contig49591_RCactivating Hypothetical protein 1315 5283 transcription factor 7interacting protein 2 Contig49631_RC ATP11C ATPase, Class VI, Hydrolase,Transmembrane, 1316 5284 type 11C Phosphorylation, Magnesium, Metal-binding, ATP-binding, Multigene family, Alternative splicingContig49667_RC deaminase domain 1317 5285 containing 1 Contig49673_RCAD034 RIO kinase 1 (yeast) Kinase, Hypothetical protein 1318 5286Contig49725_RC LOC51611 CDNA clone Transferase, Methyltransferase, 13195287 IMAGE: 4821863, Alternative splicing, Hypothetical partial cdsprotein Contig49738_RC ATIC aj25f09.s1 Purine biosynthesis, Transferase,1320 5288 Soares_testis_NHT Hydrolase, Multifunctional enzyme Homosapiens cDNA clone 1391369 3′, mRNA sequence. Contig49744_RC FLJ14166hypothetical protein Hypothetical protein 1321 5289 FLJ14166Contig49756_RC Transcribed 1322 5290 sequences Contig49849_RC C6orf1hypothetical protein Hypothetical protein 1323 5291 MGC57858 Contig49855MGC33338 hypothetical protein Hypothetical protein 1324 5292 MGC33338Contig49875 Full length insert 1325 5293 cDNA YN61C04 Contig49948_RCMGC27385 potassium channel Hypothetical protein 1326 5294tetramerisation domain containing 6 Contig49966_RC CDNA FLJ31683 fis,1327 5295 clone NT2RI2005353 Contig49983_RC MGC3121 hypothetical proteinHypothetical protein 1328 5296 MGC3121 Contig49991_RC Transcribed 13295297 sequence with weak similarity to protein ref: NP_062553.1 (H.sapiens) hypothetical protein FLJ11267 [Homo sapiens] Contig50039_RCKIAA0140 similar to CG9643- Hypothetical protein 1330 5298 PAContig50106_RC KIAA1708 kinesin family Hypothetical protein 1331 5299member 21A Contig50117_RC Transcribed 1332 5300 sequences Contig50134_RCBITE p10-binding protein Hypothetical protein 1333 5301 Contig50137_RCMGC12992 hypothetical protein GTP-binding, Microtubules, Multigene 13345302 MGC12992 family Contig50177_RC MBLR ring finger proteinHypothetical protein, Metal-binding, 1335 5303 134 Zinc, Zinc-fingerContig50190_RC LOC51005 MRNA; cDNA Glycoprotein, Ion transport, Ionic1336 5304 DKFZp313E2215 channel, Transmembrane (from cloneDKFZp313E2215) Contig50194_RC C9orf16 chromosome 9 open Hypotheticalprotein, Coiled coil 1337 5305 reading frame 16 Contig50211_RC MGC35392hypothetical protein Hypothetical protein 1338 5306 MGC35392Contig50220_RC FLJ13231 hypothetical protein Hypothetical protein 13395307 FLJ13231 Contig50232_RC DDX31 DEAD (Asp-Glu-Ala- ATP-binding,Helicase, Hydrolase, 1340 5308 Asp) box polypeptide Hypothetical protein31 Contig50249_RC MGC23908 similar to RNA Hypothetical protein 1341 5309polymerase B transcription factor 3 Contig50272_RC Transcribed 1342 5310sequences Contig50273_RC hypothetical protein Hypothetical protein 13435311 LOC255783 Contig50275_RC gm117 gm117 1344 5312 Contig50293_RCEGFR-RS rhomboid family 1 Hypothetical protein, Receptor 1345 5313(Drosophila) Contig50295_RC FLJ12541 stimulated by Hypothetical protein1346 5314 retinoic acid gene 6 Contig50298_RC FLJ32370 hypotheticalprotein Hypothetical protein 1347 5315 FLJ32370 Contig50324_RC LOC51044CDNA FLJ25011 fis, 1348 5316 clone CBL01244 Contig50337_RC MGC4645hypothetical protein Hypothetical protein, Repeat, WD 1349 5317 MGC4645repeat Contig50381_RC CD109 CD109 antigen (Gov Hypothetical protein 13505318 platelet alloantigens) Contig50391_RC Transcribed 1351 5319sequence with moderate similarity to protein ref: NP_060312.1 (H.sapiens) hypothetical protein FLJ20489 [Homo sapiens] Contig50436_RCCDNA FLJ37094 fis, 1352 5320 clone BRACE2018337 Contig50465_RCTranscribed 1353 5321 sequences Contig50483 KIAA1718 KIAA1718 proteinHypothetical protein 1354 5322 Contig50490_RC LOC90678 leucine richrepeat Hypothetical protein 1355 5323 and sterile alpha motif containing1 Contig50501_RC coronin, actin Actin-binding, Repeat, WD repeat, 13565324 binding protein, 2A Coiled coil Contig50595_RC hypothetical proteinHypothetical protein 1357 5325 LOC147111 Contig50605_RC wj49g02.x1 13585326 NCI_CGAP_Lu19 Homo sapiens cDNA clone IMAGE: 2406194 3′, mRNAsequence. Contig50669_RC KIF9 kinesin family Hypothetical protein, Motorprotein, 1359 5327 member 9 Microtubule, ATP-binding, Coiled coil,Alternative splicing Contig50675 BA108L7.2 similar to rat Hypotheticalprotein, Transport, Iron 1360 5328 tricarboxylate transport,Mitochondrion, carrier-like protein Transmembrane Contig50687_RC MINA53hypothetical protein Hypothetical protein 1361 5329 DKFZp667G2110Contig506_RC KIAA1821 rab11-family Hypothetical protein 1362 5330interacting protein 4 Contig50728_RC Transcribed 1363 5331 sequence withweak similarity to protein ref: NP_071385.1 (H. sapiens) hypotheticalprotein FLJ20958 [Homo sapiens] Contig50747_RC MGC23427 BTB (POZ) domain1364 5332 containing 14A Contig50759 DKFZp761P1121 hypothetical proteinHypothetical protein, RNA-binding, 1365 5333 DKFZp761P1121 Repeat,Alternative splicing Contig50787_RC FLJ31528 hypothetical proteinHypothetical protein 1366 5334 FLJ31528 Contig50814_RC MGC27027 immuneassociated Hypothetical protein 1367 5335 nucleotide Contig50831_RCLOC389865 1368 5336 (LOC389865), mRNA Contig50838_RC LOC120224hypothetical protein Hypothetical protein 1369 5337 BC016153Contig50846_RC zinc finger CCCH Hypothetical protein 1370 5338 typedomain containing 5 Contig50848_RC KIAA1705 DDHD domain Lipiddegradation, Hydrolase, 1371 5339 containing 1 Alternative splicingContig50891_RC Homo sapiens, ATP-binding, Kinase, 1372 5340p21/Cdc42/Rac1- Serine/threonine-protein kinase, activated kinase 1Transferase, Apoptosis, (STE20 homolog, Phosphorylation, 3D-structureyeast), clone MGC: 51883 IMAGE: 5763796, mRNA, complete cds.Contig50905_RC CDNA FLJ42250 fis, 1373 5341 clone TKIDN2007828Contig50920_RC KIAA1847 Homo sapiens Hypothetical protein, Zinc-finger,1374 5342 mRNA for KIAA1847 Alternative splicing protein, partial cds.Contig51020_RC MGC21874 transcriptional Hypothetical protein 1375 5343adaptor 2 (ADA2 homolog, yeast)- beta Contig51026_RC DKFZp762A2013quiescin Q6-like 1 Hypothetical protein, Signal 1376 5344 Contig51068_RCCDNA clone 1377 5345 IMAGE: 5286843, partial cds Contig51070_RC FLJ25005FLJ25005 protein Hypothetical protein 1378 5346 Contig51087_RC NPEPL1aminopeptidase-like 1 Hydrolase, Aminopeptidase, Zinc, 1379 5347Manganese, Alternative splicing Contig51103_RC JFC1 NADPH oxidase-Hypothetical protein, Repeat, 1380 5348 related, C2 domain- Alternativesplicing containing protein Contig51105_RC Transcribed 1381 5349sequence with weak similarity to protein ref: NP_062553.1 (H. sapiens)hypothetical protein FLJ11267 [Homo sapiens] Contig51128_RC MGC35182hypothetical protein Hypothetical protein 1382 5350 MGC35182Contig51151_RC ASP AKAP-associated 1383 5351 sperm proteinContig51163_RC hypothetical protein Hypothetical protein 1384 5352MGC45871 Contig51170_RC bruno-like 4, RNA Hypothetical protein 1385 5353binding protein (Drosophila) Contig51254_RC CLG likely ortholog ofHypothetical protein 1386 5354 mouse common-site lymphoma/leukemia GEFContig51288_RC NR2C2 nuclear receptor Receptor, Transcriptionregulation, 1387 5355 subfamily 2, group DNA-binding, Nuclear protein,Zinc- C, member 2 finger Contig51291_RC KIAA1977 KIAA1977 proteinHypothetical protein, ANK repeat, 1388 5356 Repeat Contig51297_RCFLJ33817 hypothetical protein Hypothetical protein, Repeat, WD 1389 5357FLJ33817 repeat Contig51311_RC KDELC1 KDEL (Lys-Asp-Glu- Hypotheticalprotein 1390 5358 Leu) containing 1 Contig51373_RC KIAA1688 KIAA1688protein Repeat 1391 5359 Contig51414_RC FLJ23441 hypothetical proteinHypothetical protein 1392 5360 FLJ23441 Contig51417_RC SHANK3 SH3 andmultiple SH3-binding, Coiled coil, 1393 5361 ankyrin repeat Chromosomaltranslocation domains 3 Contig51449_RC RAB15, member Hypotheticalprotein, Plasmid 1394 5362 RAS onocogene family Contig51519_RC spasticparaplegia 6 Hypothetical protein 1395 5363 (autosomal dominant)Contig51526_RC RAB39B RAB39B, member GTP-binding, Lipoprotein, 1396 5364RAS oncogene Prenylation, Transport, Protein family transportContig51553_RC MGC3200 hypothetical protein Hypothetical protein 13975365 MGC3200 Contig51567_RC hypothetical protein Hypothetical protein1398 5366 MGC33371 Contig51621_RC ubiquitin specific Hypotheticalprotein, Ubl conjugation 1399 5367 protease 13 pathway, Hydrolase, Thiolprotease, (isopeptidase T-3) Multigene family, Repeat Contig51625_RCClone Hypothetical protein 1400 5368 IMAGE: 3868989, mRNA, partial cdsContig51660_RC IFRG28 28 kD interferon Transmembrane 1401 5369responsive protein Contig51687_RC KRTDAP KIPV467 1402 5370Contig51723_RC Splicing factor, 1403 5371 arginine/serine-rich, 46 kDContig51726_RC FLJ20739 Transcribed Hypothetical protein 1404 5372sequence with weak similarity to protein pir: S41161 (H. sapiens) S41161keratin 9, cytoskeletal - human Contig51737_RC CDNA FLJ38931 fis, 14055373 clone NT2NE2013189 Contig51740_RC FLJ33282 amyotrophic lateralHypothetical protein 1406 5374 sclerosis 2 (juvenile) chromosome region,candidate 4 Contig51742_RC RISC likely homolog of rat Hydrolase,Carboxypeptidase, 1407 5375 and mouse retinoid- Signal, Glycoprotein,Alternative inducible serine splicing carboxypeptidase Contig51757 lin-7homolog A (C. elegans) 1408 5376 Contig51795_RC TGFBI CDNA FLJ37830 fis,Extracellular matrix, Signal, Repeat, 1409 5377 clone Cell adhesion,Disease mutation, BRSSN2009395 Amyloid, Vision Contig51800 Transcribed1410 5378 sequence with strong similarity to protein pdb: 1BGM (E. coli)O Chain O, Beta-Galactosidase Contig51809_RC C21orf63 chromosome 21Signal, Transmembrane, Repeat, 1411 5379 open reading frameGlycoprotein, Lectin, Alternative 63 splicing Contig51821_RC TAF4B TAF4bRNA Transcription regulation, Nuclear 1412 5380 polymerase II, TATAprotein box binding protein (TBP)-associated factor, 105 kDaContig51882_RC MGC11335 hypothetical protein Hypothetical protein 14135381 MGC11335 Contig51888_RC pannexin 1 Gap junction, Transmembrane,1414 5382 Polymorphism Contig51896_RC HT021 HT021 1415 5383Contig51917_RC WBSCR14 Full length insert Transcription regulation,Repressor, 1416 5384 cDNA clone Nuclear protein, DNA-binding, YI46G04Williams-Beuren syndrome, Alternative splicing Contig51929 PAI-1mRNA-binding Hypothetical protein 1417 5385 protein Contig51964_RCFLJ40629 hypothetical protein Hypothetical protein 1418 5386 FLJ40629Contig51967_RC solute carrier family Transport, Symport, 1419 5387 16(monocarboxylic Transmembrane, Multigene family acid transporters),member 6 Contig51974_RC Transcribed Hypothetical protein, Phospholipid1420 5388 sequences biosynthesis, Transferase, Acyltransferase,Transmembrane Contig52062_RC FLJ31978 hypothetical protein Hypotheticalprotein 1421 5389 FLJ31978 Contig52099_RC CDNA FLJ41881 fis, 1422 5390clone OCBBF2021833 Contig52186_RC zinc finger protein 67 Metal-binding,Zinc, Zinc-finger 1423 5391 homolog (mouse) Contig52199_RC CDNA FLJ12540fis, 1424 5392 clone NT2RM4000425 Contig52220_RC CDNA FLJ25573 fis, 14255393 clone JTH06531 Contig52232_RC DERMO1 twist homolog 2Differentiation, Developmental 1426 5394 (Drosophila) protein, Nuclearprotein, DNA- binding, Repressor, Transcription regulationContig52242_RC CDNA FLJ12345 fis, Hypothetical protein 1427 5395 cloneMAMMA1002294 Contig52312_RC TFEB transcription factor Transcriptionregulation, DNA- 1428 5396 EB binding, Nuclear protein, Alternativesplicing Contig52317_RC hypothetical protein Hypothetical protein,Ubiquinone 1429 5397 LOC91942 Contig52320 Full length insert 1430 5398cDNA clone YX81F03 Contig52336_RC MGC2488 homolog of yeast Hypotheticalprotein 1431 5399 Mis12 Contig52358_RC Transcribed 1432 5400 sequencesContig52405_RC EDG3 endothelial G-protein coupled receptor, 1433 5401differentiation, Transmembrane, Glycoprotein sphingolipid G-protein-coupled receptor, 3 Contig52414_RC CAMTA1 calmodulin bindingHypothetical protein, ANK repeat, 1434 5402 transcription Repeatactivator 1 Contig52443 hypothetical protein 1435 5403 INM01Contig52482_RC PNPASE polyribonucleotide Hypothetical protein,Exonuclease, 1436 5404 nucleotidyltransferase 1 Nucleotidyltransferase,Transferase Contig52486_RC PPARAL CDNA FLJ31089 fis, 1437 5405 cloneIMR321000092 Contig52520_RC MRNA full length 1438 5406 insert cDNA cloneEUROIMAGE 2068962 Contig52544_RC MGC17515 hypothetical proteinHypothetical protein 1439 5407 MGC17515 Contig52553_RC LOC197336 similarto RIKEN Hypothetical protein, Repeat, WD 1440 5408 cDNA 3230401M21repeat [Mus musculus] Contig52561_RC Cas-Br-M (murine) Hypotheticalprotein, Ligase, Ubl 1441 5409 ecotropic retroviral conjugation pathway,Proto- transforming oncogene, Zinc-finger, SH2 domain, sequencePhosphorylation, Calcium-binding, 3D-structure Contig52565_RC MAXdimerization Nuclear protein, DNA-binding, 1442 5410 protein 1Transcription regulation, Repressor, 3D-structure Contig52570_RC CDNAFLJ41853 fis, 1443 5411 clone NT2RI3004161 Contig52579_RC breast cancer1444 5412 membrane protein 101 Contig52609_RC hypothetical proteinHypothetical protein 1445 5413 FLJ33814 Contig52623_RC FLJ12888chromosome 9 open Hypothetical protein 1446 5414 reading frame 76Contig52648_RC MGC2404 acyl-Coenzyme A ANK repeat, Repeat 1447 5415binding domain containing 6 Contig52659_RC hypothetical proteinHypothetical protein 1448 5416 LOC255104 Contig52715_RC Transcribed 14495417 sequences Contig52720_RC MGC2714 hypothetical protein Hypotheticalprotein 1450 5418 MGC2714 Contig52722_RC MGC3020 hypothetical proteinHypothetical protein 1451 5419 MGC3020 Contig5274_RC C21orf91 chromosome21 Polymorphism 1452 5420 open reading frame 91 Contig52777_RCTranscribed 1453 5421 sequence with strong similarity to protein ref:NP_286085.1 (E. coli) beta-D- galactosidase [Escherichia coli O157:H7EDL933] Contig52786_RC ZNF198 zinc finger protein Hypothetical protein,Transcription 1454 5422 198 regulation, Nuclear protein, Chromosomaltranslocation, Repeat, Zinc-finger Contig52792_RC MGC3062 phosducin-like3 1455 5423 Contig52814_RC Transcribed 1456 5424 sequencesContig52891_RC membrane Hypothetical protein 1457 5425 associatedguanylate kinase interacting protein- like 1 Contig52914_RC MGC4663cytochrome P450, Hypothetical protein 1458 5426 family 2, subfamily R,polypeptide 1 Contig52924_RC FLJ14827 hypothetical protein Hypotheticalprotein 1459 5427 FLJ14827 Contig52932_RC DKFZP566D1346 hypotheticalprotein Hypothetical protein, ANK repeat, 1460 5428 DKFZp566D1346 RepeatContig52945_RC KIAA1946 KIAA1946 protein Hypothetical protein 1461 5429Contig52971_RC SCAMP5 secretory carrier Hypothetical protein 1462 5430membrane protein 5 Contig52993_RC MAP3K3 mitogen-activated Hypotheticalprotein, ATP-binding, 1463 5431 protein kinase Transferase,Serine/threonine- kinase kinase 3 protein kinase Contig52994_RCTranscribed 1464 5432 sequence with weak similarity to protein ref:NP_055301.1 (H. sapiens) neuronal thread protein [Homo sapiens]Contig53047_RC TTYH1 tweety homolog 1 1465 5433 (Drosophila)Contig53066_RC ARL5 ADP-ribosylation GTP-binding, Multigene family 14665434 factor-like 5 Contig53072_RC KIAA1474 zinc finger proteinHypothetical protein, Metal-binding, 1467 5435 537 Zinc, Zinc-fingerContig53080_RC CDNA FLJ31655 fis, 1468 5436 clone NT2RI2004284Contig53149_RC RIN3 Ras and Rab GTPase activation, SH2 domain, 1469 5437interactor 3 Alternative splicing, Plasmid Contig53177_RC CDNA FLJ90571fis, 1470 5438 clone OVARC1001725, highly similar to Homo sapienspatched related protein TRC8 (TRC8) gene. Contig53211_RC FLJ11588hypothetical protein Hypothetical protein 1471 5439 FLJ11588 Contig53223PPP1R15B protein phosphatase Hypothetical protein 1472 5440 1,regulatory (inhibitor) subunit 15B Contig53226_RC hypothetical proteinHypothetical protein 1473 5441 DKFZp762C1112 Contig53243_RC hypotheticalprotein Hypothetical protein 1474 5442 LOC257106 Contig53253_RC WWP2Nedd-4-like Ubl conjugation pathway, Ligase, 1475 5443 ubiquitin-proteinRepeat ligase Contig53260_RC hypothetical protein Hypothetical protein1476 5444 LOC196264 Contig53307_RC LOC51184 Homo sapiens Hypotheticalprotein 1477 5445 mRNA full length insert cDNA clone EUROIMAGE 1635059.Contig53323 KIAA1608 KIAA1608 Hypothetical protein 1478 5446Contig53342_RC Transcribed 1479 5447 sequences Contig53349_RC FLJ12287hypothetical protein Hypothetical protein, Signal, 1480 5448 FLJ12287similar to Transmembrane, Immunoglobulin semaphorins domain, Multigenefamily, Neurogenesis, Developmental protein, Glycoprotein Contig53355_RCMGC10870 hypothetical protein 1481 5449 MGC10870 Contig53410_RC FLJ14596chromosome 9 open Hypothetical protein 1482 5450 reading frame 54Contig53439_RC FLJ22457 hypothetical protein Hypothetical protein 14835451 FLJ22457 Contig53460_RC CDNA FLJ30010 fis, 1484 5452 clone3NB692000154 Contig5348_RC Transcribed 1485 5453 sequence with weaksimilarity to protein sp: Q13892 (H. sapiens) BT33_HUMAN Transcriptionfactor BTF3 homolog 3 Contig53517_RC PJA1 praja 1 Ubl conjugationpathway, Ligase, 1486 5454 Zinc-finger, Alternative splicingContig53555_RC myotubularin related Hydrolase, Zinc-finger, Alternative1487 5455 protein 3 splicing, Hypothetical protein Contig53566_RC LANCL2LanC lantibiotic Hypothetical protein 1488 5456 synthetase componentC-like 2 (bacterial) Contig53585_RC CG005 phosphonoformate Hypotheticalprotein 1489 5457 immuno-associated protein 5 Contig53615_RC MGC4692hypothetical protein 1490 5458 LOC283871 Contig53635_RC FLJ39514 sec1family domain Hypothetical protein 1491 5459 containing 2 Contig53641_RCMAGE-E1 melanoma antigen, Hypothetical protein 1492 5460 family D, 4Contig53696_RC MDS006 x 006 protein 1493 5461 Contig53709_RCadaptor-related Golgi stack, Protein transport, 1494 5462 proteincomplex 1, Transport, Coated pits, Endocytosis, gamma 1 subunitPolymorphism, 3D-structure, Hypothetical protein Contig53719_RC FLJ30596hypothetical protein Hypothetical protein 1495 5463 FLJ30596Contig53746_RC DRLM nucleosome Hypothetical protein 1496 5464 assemblyprotein 1- like 5 Contig53819_RC MGC11296 breast cancer 1497 5465metastasis- suppressor 1-like Contig53823_RC FLJ31295 hypotheticalprotein Metal-binding, Zinc, Zinc-finger, 1498 5466 FLJ31295Hypothetical protein Contig53829 MGC3123 hypothetical proteinHypothetical protein 1499 5467 MGC3123 Contig53852_RC KIAA1577 zincfinger, SWIM Hypothetical protein 1500 5468 domain containing 6Contig53884_RC LOC59346 PDZ and LIM Hypothetical protein, LIM domain,1501 5469 domain 2 (mystique) Metal-binding, Zinc Contig53909_RCMGC23947 hypothetical protein Hypothetical protein 1502 5470 MGC23947Contig5392_RC Transcribed 1503 5471 sequences Contig53944_RC MI-ER1putative NFkB Hypothetical protein 1504 5472 activating protein 373Contig53985_RC FLJ30596 hypothetical protein Hypothetical protein 15055473 FLJ30596 Contig54010_RC MDS024 chromosome 6 open 1506 5474 readingframe 75 Contig54012_RC SAS10 MRNA; cDNA Hypothetical protein 1507 5475DKFZp686C2051 (from clone DKFZp686C2051) Contig54048_RC GC1 solutecarrier family Mitochondrion, Inner membrane, 1508 5476 25(mitochondrial Repeat, Transmembrane, Transport, carrier: glutamate),Symport member 22 Contig54066_RC DEDD2 death effector DNA-binding,Hypothetical protein 1509 5477 domain containing 2 Contig54110_RCsplicing factor, mRNA processing, mRNA splicing, 1510 5478arginine/serine-rich 1 Nuclear protein, RNA-binding, (splicing factor 2,Repeat, Alternative splicing, alternate splicing Acetylation,Phosphorylation factor) Contig54113_RC FLJ11785 Rad50-interactingHypothetical protein 1511 5479 protein 1 Contig54137_RC zinc fingerprotein 84 Transcription regulation, DNA- 1512 5480 (HPF2) binding,Zinc-finger, Metal-binding, Nuclear protein, Repeat Contig54184_RCMGC955 hypothetical protein Hypothetical protein 1513 5481 MGC955Contig54317_RC MGC29956 hypothetical protein Hypothetical protein 15145482 MGC29956 Contig54321_RC DDX33 DEAH (Asp-Glu-Ala- Hypotheticalprotein, ATP-binding, 1515 5483 His) box polypeptide Helicase, Hydrolase33 Contig54342_RC MGC13096 hypothetical protein Cytokine, Disease 15165484 MGC13096 mutation, Gluconeogenesis, Glycolysis, Growth factor,Isomerase, Neurone Contig54371_RC GKAP42 protein kinase Hypotheticalprotein, Kinase 1517 5485 anchoring protein GKAP42 Contig54463_RC CDNAFLJ12874 fis, 1518 5486 clone NT2RP2003769 Contig54503_RC kelch-like 11Hypothetical protein 1519 5487 (Drosophila) Contig54531_RC Homo sapienscDNA 1520 5488 FLJ38849 fis, clone MESAN2008936. Contig54559_RC ankyrinrepeat and ANK repeat, Repeat 1521 5489 BTB (POZ) domain containing 1Contig54563_RC KNSL5 kinesin family Motor protein, Cell division, 15225490 member 23 Microtubule, ATP-binding, Coiled coil, Mitosis, Cellcycle, Nuclear protein Contig54581_RC tumor suppressor 1523 5491 TSBF1Contig54609_RC PANK3 pantothenate kinase 3 Transferase, Kinase,ATP-binding, 1524 5492 Coenzyme A biosynthesis Contig54614_RC FLJ14007hypothetical protein Hypothetical protein 1525 5493 FLJ14007Contig54659_RC HCCA2 HCCA2 protein Hypothetical protein 1526 5494Contig54667_RC ERAP140 nuclear receptor Receptor, Hypothetical protein1527 5495 coactivator 7 Contig54680_RC nucleotide-binding Hypotheticalprotein 1528 5496 oligomerization domains 27 Contig54686_RC zinc fingerprotein Hypothetical protein 1529 5497 598 Contig54716_RC KIAA0863KIAA0863 protein Hypothetical protein, Metal-binding, 1530 5498 Zinc,Zinc-finger Contig54718_RC FLJ37562 hypothetical protein Hypotheticalprotein 1531 5499 FLJ37562 Contig54729_RC chromosome 10 Hypotheticalprotein 1532 5500 open reading frame 30 Contig54751_RC VIK vav-1interacting Metal-binding, Zinc, Zinc-finger, 1533 5501 Kruppel-likeprotein Hypothetical protein Contig54757_RC hypothetical proteinHypothetical protein 1534 5502 LOC129293 Contig54802_RC GPR108 Gprotein-coupled Hypothetical protein 1535 5503 receptor 108Contig54829_RC TJP3 tight junction protein Hypothetical protein 15365504 3 (zona occludens 3) Contig54893_RC APOBEC3G apolipoprotein BHypothetical protein 1537 5505 mRNA editing enzyme, catalyticpolypeptide-like 3G Contig54915_RC DR1 Hypothetical gene Transcription,Phosphorylation, 1538 5506 supported by Nuclear protein, 3D-structureAL832786 (LOC400762), mRNA Contig54932_RC BIVM basic, Hypotheticalprotein 1539 5507 immunoglobulin-like variable motif containingContig54961_RC lemur tyrosine Hypothetical protein, ATP-binding, 15405508 kinase 2 Kinase, Transferase, Tyrosine- protein kinaseContig5498_RC C17orf26 solute carrier family Hypothetical protein 15415509 39 (metal ion transporter), member 11 Contig54999_RC FLJ12994hypothetical protein Hypothetical protein 1542 5510 FLJ12994 Contig55004DKFZP564O0463 mitochondrial folate Mitochondrion, Inner membrane, 15435511 transporter/carrier Repeat, Transmembrane, Transport Contig55022_RCALP asparaginase like 1 Hypothetical protein 1544 5512 Contig55038_RCMCOLN1 mucolipin 1 Ionic channel, Transmembrane, 1545 5513 Hypotheticalprotein Contig55044_RC DECR2 2,4-dienoyl CoA Oxidoreductase,Hypothetical protein 1546 5514 reductase 2, peroxisomal Contig55069_RCHypothetical gene 1547 5515 supported by BC040598 (LOC400960), mRNAContig55079_RC FLJ21613 corneal wound Hypothetical protein 1548 5516healing-related protein Contig55114_RC chromosome 6 open Hypotheticalprotein 1549 5517 reading frame 89 Contig55121_RC P5326 hypotheticalprotein Hypothetical protein 1550 5518 p5326 Contig5513_RC Transcribed1551 5519 sequences Contig55181_RC LOC115509 hypothetical proteinHypothetical protein, Metal-binding, 1552 5520 BC014000 Zinc,Zinc-finger Contig55193_RC HS6ST1 heparan sulfate 6-O- Transferase 15535521 sulfotransferase 1 Contig55254_RC LOC220074 Hypothetical 55.1 kDa1554 5522 protein F09G8.5 in chromosome III Contig55265_RC ets variantgene 6 Transcription regulation, Repressor, 1555 5523 (TEL oncogene)Nuclear protein, DNA-binding, Phosphorylation, Proto-oncogene,Chromosomal translocation, 3D- structure Contig55334_RC DKFZp547C195hypothetical protein Hypothetical protein 1556 5524 DKFZp547C195Contig55337_RC MGC2454 chromosome 2 open Hypothetical protein, 1557 5525reading frame 8 Methyltransferase, Transferase Contig55351_RChypothetical protein Hypothetical protein 1558 5526 MGC45871Contig55365_RC CDNA clone 1559 5527 IMAGE: 6702802, partial cdsContig55375_RC C1QTNF6 C1q and tumor Collagen, Signal 1560 5528 necrosisfactor related protein 6 Contig55377_RC DKFZp761H0421 RUN domainHypothetical protein 1561 5529 containing 1 Contig55397_RC CSPG6 sterilealpha motif Hypothetical protein, ANK repeat, 1562 5530 domaincontaining 6 Repeat Contig55468_RC solute carrier family Hypotheticalprotein 1563 5531 9 (sodium/hydrogen exchanger), isoform 9Contig55487_RC solute carrier family Hypothetical protein 1564 5532 39(zinc transporter), member 10 Contig55522 LOC400236 1565 5533(LOC400236), mRNA Contig55539_RC GAAI470 Hypothetical protein 1566 5534Contig55574_RC KIAA1940 KIAA1940 protein Hypothetical protein 1567 5535Contig55575_RC SDS3 likely ortholog of Hypothetical protein 1568 5536mouse Sds3 Contig55618_RC MGC4825 hypothetical protein Hypotheticalprotein 1569 5537 MGC4825 Contig55671_RC nuclear factor of Transcriptionregulation, Activator, 1570 5538 activated T-cells, Nuclear protein,DNA-binding, cytoplasmic, Alternative splicing, Phosphorylation,calcineurin- Repeat, 3D-structure dependent 2 Contig55674_RC DUSP16LOC387840 Hydrolase, Nuclear protein, 1571 5539 (LOC387840),Hypothetical protein mRNA Contig55709_RC chromosome 14 1572 5540 openreading frame 35 Contig55712_RC hypothetical protein Hypotheticalprotein 1573 5541 LOC286257 Contig55744_RC DIRC2 disrupted in renalHypothetical protein 1574 5542 carcinoma 2 Contig55759_RC hypotheticalprotein Repeat, ANK repeat, Alternative 1575 5543 LOC145758 splicingContig55766_RC TOMM70A hypothetical protein Mitochondrion, Outermembrane, 1576 5544 LOC348801 Transmembrane, Repeat, TPR repeatContig55767_RC FLJ22662 hypothetical protein Hypothetical protein 15775545 FLJ22662 Contig55814_RC protein containing 1578 5546 single MORNmotif in testis Contig55886_RC zinc finger protein 1579 5547 181(HHZ181) Contig55940_RC MGC13010 hypothetical protein Hypotheticalprotein 1580 5548 MGC13010 Contig55944_RC FLJ20958 MRNA; cDNAHypothetical protein 1581 5549 DKFZp686A1197 (from clone DKFZp686A1197)Contig55950_RC FLJ22329 hypothetical protein Hypothetical protein 15825550 FLJ22329 Contig55966_RC DKFZP762N2316 zinc finger proteinHypothetical protein, Metal-binding, 1583 5551 462 Zinc, Zinc-fingerContig55979_RC MGC14136 chromosome 21 Hypothetical protein 1584 5552open reading frame 119 Contig55_RC protein kinase, AMP- Fatty acidbiosynthesis, 1585 5553 activated, beta 2 Phosphorylation non-catalyticsubunit Contig56036_RC CD47 CD47 antigen (Rh- Integrin, Cell adhesion,Antigen, 1586 5554 related antigen, Signal, Transmembrane,integrin-associated Glycoprotein, Alternative splicing signaltransducer) Contig56052_RC hypothetical protein 1587 5555 LOC203547Contig56056_RC TRUB1 TruB pseudouridine 1588 5556 (psi) synthase homolog1 (E. coli) Contig56061_RC DEF6 differentially 1589 5557 expressed inFDCP 6 homolog (mouse) Contig56082_RC RNU2 Homo sapiens Hypotheticalprotein 1590 5558 mRNA; cDNA DKFZp666D074 (from clone DKFZp666D074).Contig56147_RC hypothetical protein Hypothetical protein 1591 5559LOC338799 Contig56167_RC BAALC brain and acute Hypothetical protein 15925560 leukemia, cytoplasmic Contig56179_RC MGC15523 hypothetical proteinHypothetical protein 1593 5561 MGC15523 Contig56229 likely ortholog ofHypothetical protein 1594 5562 mouse zinc finger protein EZIContig56234_RC IMAGE3451454 SVAP1 protein Hypothetical protein 1595 5563Contig56242_RC FLJ23221 hypothetical protein Hypothetical protein 15965564 FLJ23221 Contig56253_RC FLJ21087 brix domain Nuclear protein 15975565 containing 1 Contig56263_RC FLJ21080 SET and MYND Zinc-finger,Hypothetical protein 1598 5566 domain containing 3 Contig56298_RCFLJ13154 hypothetical protein Hypothetical protein 1599 5567 FLJ13154Contig56303_RC LOC51112 v-abl Abelson Transferase, Tyrosine-protein 16005568 murine leukemia kinase, Proto-oncogene, ATP- viral oncogenebinding, Phosphorylation, SH2 homolog 2 (arg, domain, SH3 domain,Alternative Abelson-related splicing gene) Contig56334_RC RAI16 retinoicacid induced Hypothetical protein 1601 5569 16 Contig56350_RC MGC4607cerebral cavernous Hypothetical protein 1602 5570 malformation 2Contig56390_RC MGC26847 sushi domain 1603 5571 containing 3Contig56395_RC FLJ14624 hypothetical protein Hypothetical protein 16045572 FLJ14624 Contig5639_RC phosphorylase, Transferase,Glycosyltransferase, 1605 5573 glycogen; liver (Hers Carbohydratemetabolism, Glycogen disease, glycogen metabolism, Allosteric enzyme,storage disease type Pyridoxal phosphate, VI) Phosphorylation, Glycogenstorage disease, Disease mutation, Polymorphism, 3D-structureContig56503_RC MGC9753 CAB2 protein Hypothetical protein 1606 5574Contig56527_RC FLJ20758 protein Hypothetical protein 1607 5575Contig56541_RC LSFR2 dolichyl 1608 5576 pyrophosphate phosphatase 1Contig56544_RC H3F3A hypothetical protein Nuclear protein, Chromosomal1609 5577 FLJ20403 protein, DNA-binding, Nucleosome core, Multigenefamily Contig56572_RC DKFZP564B1162 hypothetical protein Hypotheticalprotein 1610 5578 DKFZp564B1162 Contig56583_RC PF20 PF20 Repeat, WDrepeat, Hypothetical 1611 5579 protein Contig56587_RC HDAC10 histonedeacetylase Hydrolase, Nuclear protein, 1612 5580 10 Chromatinregulator, Transcription regulation, Repressor, Polymorphism,Alternative splicing Contig565_RC CDNA FLJ31683 fis, 1613 5581 cloneNT2RI2005353 Contig56623_RC Cas-Br-M (murine) Hypothetical protein,Ligase, Ubl 1614 5582 ecotropic retroviral conjugation pathway, Proto-transforming oncogene, Zinc-finger, SH2 domain, sequencePhosphorylation, Calcium-binding, 3D-structure Contig56662_RC MGC10963THAP domain Zinc-finger, DNA-binding 1615 5583 containing 7Contig56671_RC FLJ12761 mSin3A-associated Hypothetical protein 1616 5584protein 130 Contig56716_RC KIAA1754 KIAA1754 Hypothetical protein 16175585 Contig56735_RC CDNA FLJ90790 fis, Hypothetical protein 1618 5586clone THYRO1001529, weakly similar to SERINE PALMITOYLTRANSFERASE 2 (EC2.3.1.50). Contig56781_RC MGC11349 hypothetical protein Hypotheticalprotein, Metal-binding, 1619 5587 MGC11349 Zinc, Zinc-fingerContig56823_RC Transcribed 1620 5588 sequence with moderate similarityto protein ref: NP_060265.1 (H. sapiens) hypothetical protein FLJ20378[Homo sapiens] Contig56944_RC ASH1 ash1 (absent, small, Hypotheticalprotein 1621 5589 or homeotic)-like (Drosophila) Contig57011_RC CDA11CDA11 protein Hypothetical protein 1622 5590 Contig57017_RC TFB2Mtranscription factor Hypothetical protein 1623 5591 B2, mitochondrialContig57036_RC hypothetical protein Fatty acid biosynthesis, Biotin,1624 5592 LOC283445 Ligase, Multifunctional enzyme, ATP-binding,Phosphorylation, Alternative splicing Contig57057_RC MAP3K3 hypotheticalprotein Hypothetical protein, LIM domain, 1625 5593 MGC10986Metal-binding, Zinc Contig57076_RC FBXO32 F-box only protein Ublconjugation pathway 1626 5594 32 Contig57081_RC MSI2 musashi homolog 2Hypothetical protein 1627 5595 (Drosophila) Contig57090_RC Full lengthinsert 1628 5596 cDNA clone YZ93G08 Contig5716_RC CDNA FLJ38396 fis,1629 5597 clone FEBRA2007957 Contig57173_RC KIAA1737 KIAA1737Hypothetical protein 1630 5598 Contig571_RC ST6GALNAC6 CMP-NeuAC:(beta)-Glycosyltransferase, Transferase, 1631 5599 N- Hypothetical proteinacetylgalactosaminide (alpha)2,6- sialyltransferase member VIContig57226_RC tubulin, beta, 2 GTP-binding, Hypothetical protein, 16325600 Microtubule, Multigene family Contig57239_RC EPI64 KIAA0114 geneHypothetical protein 1633 5601 product Contig57270_RC ABCC4 ATP-bindingATP-binding, Glycoprotein, 1634 5602 cassette, sub-family Transmembrane,Transport, Repeat C (CFTR/MRP), member 4 Contig57290_RC hypotheticalprotein 1635 5603 LOC286334 Contig57417 LOC80298 transcriptionHypothetical protein 1636 5604 termination factor- like proteinContig57436_RC PPP2R5E protein phosphatase Phosphorylation, Multigenefamily 1637 5605 2, regulatory subunit B (B56), epsilon isoformContig57458_RC IL6R interleukin 6 receptor Receptor, Transmembrane, 16385606 Glycoprotein, Immunoglobulin domain, Repeat, Alternative splicing,Signal, 3D-structure Contig57493_RC MGC4399 mitochondrial carrier 16395607 protein Contig57562_RC M11S1 membrane GPI-anchor 1640 5608component, chromosome 11, surface marker 1 Contig57579 ABTB1 ankyrinrepeat and ANK repeat, Repeat 1641 5609 BTB (POZ) domain containing 1Contig57625_RC FLJ14225 polycystic kidney Hypothetical protein 1642 5610disease 1-like Contig57822_RC CDNA clone 1643 5611 IMAGE: 5286019,partial cds Contig57825_RC MGC18216 hypothetical protein Hypotheticalprotein 1644 5612 MGC18216 Contig57840_RC MBP CDNA clone Hypotheticalprotein, Myelin, 1645 5613 MGC: 70813 Structural protein, Acetylation,IMAGE: 6060520, Methylation, Phosphorylation, complete cdsCitrullination, Autoimmune encephalomyelitis, 3D-structure, Alternativesplicing Contig57957_RC COL5A2 similar to RIKEN Hypothetical protein1646 5614 cDNA 5730578N08 gene Contig58042_RC CDNA FLJ39602 fis, 16475615 clone SKNSH2005061 Contig58113_RC FLJ14005 hypothetical proteinHypothetical protein 1648 5616 LOC286044 Contig58123_RC NFYB nucleartranscription Transcription regulation, DNA- 1649 5617 factor Y, betabinding, Activator, Nuclear protein, 3D-structure Contig58145_RC YEAsolute carrier family Hypothetical protein 1650 5618 35, member B4Contig58156_RC C20orf167 deoxynucleotidyltransferase, Nuclear protein,Polymorphism 1651 5619 terminal, interacting protein 1 Contig58193_RCTCF7L2 transcription factor Transcription regulation, Activator, 16525620 7-like 2 (T-cell Repressor, Trans-acting factor, specific, HMG-box)Nuclear protein, DNA-binding, Wnt signaling pathway, Alternativesplicing, 3D-structure, Hypothetical protein Contig58212_RC PPARBP PPARbinding DNA-binding, Transcription 1653 5621 protein regulation,Activator, Repeat, Nuclear protein, Alternative splicing Contig58249_RCmoblak MOB1, Mps One Hypothetical protein 1654 5622 Binder kinaseactivator-like 2A (yeast) Contig58260_RC DGAT2 diacylglycerol O-Hypothetical protein, 1655 5623 acyltransferase Acyltransferase,Transferase homolog 2 (mouse) Contig58275_RC general transcription 16565624 factor IIIC, polypeptide 4, 90 kDa Contig58288_RC LOC89941 rashomolog gene Hypothetical protein, GTP-binding 1657 5625 family, memberT2 Contig58339_RC FLJ21616 MRNA; cDNA Hypothetical protein 1658 5626DKFZp686E1648 (from clone DKFZp686E1648) Contig58353_RC FLJ13089hypothetical protein Hypothetical protein 1659 5627 FLJ13089Contig58491_RC TRIP11 ah24a06.s1 Hypothetical protein, Antigen, Golgi1660 5628 Soares_parathyroid_tumor_NbHPA stack, Coiled coil, ChromosomalHomo sapiens cDNA translocation clone 1239730 3′, mRNA sequence.Contig58530_RC KIAA1560 glycerol 3-phosphate Hypothetical protein,Phospholipid 1661 5629 acyltransferase, biosynthesis, Transferase,mitochondrial Acyltransferase, Transmembrane, Mitochondrion, Transitpeptide Contig58595_RC AP1M1 adaptor-related Golgi stack, Proteintransport, 1662 5630 protein complex 1, Transport, Coated pits,Endocytosis, mu 1 subunit Phosphorylation Contig58613 VPS4B vacuolarprotein ATP-binding 1663 5631 sorting 4B (yeast) Contig58966_RC HLA-Fmajor MHC 1664 5632 histocompatibility complex, class I, FContig59120_RC FLJ37080 adhesion molecule Hypothetical protein 1665 5633AMICA Contig59127_RC PCF11 pre-mRNA cleavage mRNA processing, Nuclearprotein 1666 5634 complex II protein Pcf11 Contig59134_RC hypotheticalprotein 1667 5635 LOC283481 Contig59136_RC qp75d05.x1 1668 5636Soares_fetal_lung_NbHL19W Homo sapiens cDNA clone IMAGE: 1928841 3′similar to gb: D14531 60S RIBOSOMAL PROTEIN L9 (HUMAN); mRNA sequence.Contig59187_RC NUDT3 nudix (nucleoside Hydrolase 1669 5637 diphosphatelinked moiety X)-type motif 3 Contig5954_RC similar to RIKENHypothetical protein, Iron, Iron-sulfur 1670 5638 cDNA B230118G17 geneContig60075 FLJ32468 ESTs 1671 5639 Contig60315_RC MGC39807 organicsolute Hypothetical protein 1672 5640 transporter alpha Contig6041_RCTranscribed 1673 5641 sequences Contig60509_RC GL004 proteinHypothetical protein 1674 5642 Contig60612_RC xylosyltransferase ITransferase, Glycosyltransferase 1675 5643 Contig6064_RC Colorectalcancer- 1676 5644 related mRNA sequence Contig60981_RC p10-bindingprotein Hypothetical protein 1677 5645 Contig61061_RC RASGRP4 RAS guanylHypothetical protein 1678 5646 releasing protein 4 Contig6113_RC CDNAFLJ30090 fis, 1679 5647 clone BNGH41000015 Contig61227_RC hypotheticalprotein Hypothetical protein, Repeat, WD 1680 5648 FLJ10055 repeatContig61254_RC MGC5352 hypothetical protein Hypothetical protein 16815649 MGC5352 Contig61264_RC KIAA1833 hypothetical protein Hypotheticalprotein 1682 5650 KIAA1833 Contig61267_RC C20orf126 chromosome 20Hypothetical protein 1683 5651 open reading frame 126 Contig61815LOC51063 hypothetical protein Hypothetical protein 1684 5652 LOC51063Contig61848_RC Transcribed 1685 5653 sequence with weak similarity toprotein ref: NP_060312.1 (H. sapiens) hypothetical protein FLJ20489[Homo sapiens] Contig61915_RC MGC2803 hypothetical protein Hypotheticalprotein 1686 5654 MGC2803 Contig61975 MGC11242 hypothetical proteinHypothetical protein 1687 5655 MGC11242 Contig62149_RC chromosome 22Hypothetical protein 1688 5656 open reading frame 23 Contig6254_RCTranscribed 1689 5657 sequences Contig62568_RC MRPL24 mitochondrialRibosomal protein, Hypothetical 1690 5658 ribosomal protein protein L24Contig62588_RC hypothetical protein DNA-binding, Metal-binding, Nuclear1691 5659 LOC284323 protein, Zinc-finger Contig62628_RC EIF3S9eukaryotic Hypothetical protein, Initiation factor, 1692 5660translation initiation Protein biosynthesis, RNA-binding factor 3,subunit 9 eta, 116 kDa Contig62675_RC similar to RIKEN Hypotheticalprotein 1693 5661 1810056O20 Contig62923_RC FLJ12697 ubiquitin specificUbl conjugation pathway, Hydrolase, 1694 5662 protease 42 Thiolprotease, Multigene family Contig63026 hypothetical protein 1695 5663LOC285958 Contig63079 FLJ32332 likely ortholog of Hypothetical protein1696 5664 mouse protein phosphatase 2C eta Contig6323_RC FLJ12581 Nanoghomeobox DNA-binding, Homeobox, Nuclear 1697 5665 protein, Hypotheticalprotein Contig63304 LOC113444 hypothetical protein Hypothetical protein1698 5666 BC011880 Contig63667_RC MCPR hypothetical protein Ublconjugation pathway, Cell cycle, 1699 5667 LOC285069 Cell division,Mitosis, Repeat Contig6382_RC Transcribed 1700 5668 sequencesContig63913_RC MGC13016 coiled-coil-helix- 1701 5669 coiled-coil-helixdomain containing 6 Contig64214_RC MGC19604 similar to RIKENHypothetical protein 1702 5670 cDNA B230118G17 gene Contig64297_RCKIAA1416 KIAA1416 protein Hypothetical protein, Transcription 1703 5671regulation, Hydrolase, Helicase, Chromatin regulator, Nuclear protein,ATP-binding, DNA-binding, Repeat Contig64390 C20orf92 COMM domainHypothetical protein 1704 5672 containing 7 Contig64477 Clone 1705 5673IMAGE: 5742072, mRNA Contig64502 KIAA0303 KIAA0303 protein Hypotheticalprotein, ATP-binding, 1706 5674 Kinase, Serine/threonine-protein kinase,Transferase Contig64691 UBB ubiquitin B Hypothetical protein 1707 5675Contig64794 FLJ21156 Homo sapiens Hypothetical protein 1708 5676 cDNA:FLJ21156 fis, clone CAS09878. Contig64940_RC ORAOV1 oral cancerHypothetical protein 1709 5677 overexpressed 1 Contig65300_RC CDNAFLJ41454 fis, 1710 5678 clone BRSTN2011597 Contig65404 CKLFSF3chemokine-like Chemotaxis, Cytokine, 1711 5679 factor super family 3Transmembrane, Alternative splicing Contig65439 C20orf178 chromosome 20Hypothetical protein 1712 5680 open reading frame 178 Contig65459_RCformin binding Hypothetical protein, SH3 domain 1713 5681 protein 1Contig65478_RC phosphoglucomutase Hypothetical protein 1714 5682 2-like1 Contig65900 HMGN3 high mobility group Nuclear protein, DNA-binding,1715 5683 nucleosomal binding Hypothetical protein domain 3Contig65934_RC hypothetical gene Hypothetical protein 1716 5684supported by BC031661 Contig66003_RC MY038 retinoblastoma Hypotheticalprotein, Metal-binding, 1717 5685 binding protein 6 Zinc, Zinc-fingerContig66028_RC reversion-inducing- Signal, Glycoprotein, GPI-anchor,1718 5686 cysteine-rich protein Serine protease inhibitor, with kazalmotifs Membrane, Anti-oncogene, Repeat, Lipoprotein Contig66129_RC CDNAFLJ13276 fis, 1719 5687 clone OVARC1001040 Contig66573_RC FLJ12567 CloneHypothetical protein 1720 5688 IMAGE: 5538723, mRNA Contig66615_RC USP9YHuman S6 H-8 Ubiquitin conjugation, Hydrolase, 1721 5689 mRNA expressedin Thiol protease, Multigene family, chromosome 6- Alternative splicingsuppressed melanoma cells. Contig66632_RC hypothetical protein 1722 5690LOC339324 Contig66759_RC MGC16028 MGC16028 similar 1723 5691 to RIKENcDNA 1700019E19 gene Contig667_RC ADAM17 hypothetical protein Hydrolase,Metalloprotease, Zinc, 1724 5692 LOC285148 Signal, Glycoprotein,Zymogen, Transmembrane, SH3-binding, Phosphorylation, Alternativesplicing, 3D-structure Contig66868_RC ze63e05.s1 Soares 1725 5693 retinaN2b4HR Homo sapiens cDNA clone IMAGE: 363680 3′, mRNA sequence.Contig66904_RC MGC4368 hypothetical protein Hypothetical protein 17265694 MGC4368 Contig684_RC RPS3A ring finger protein 12 Transcriptionregulation, Zinc-finger, 1727 5695 Hypothetical protein, Metal-bindingContig693_RC NFIA nuclear factor I/A Activator, DNA replication, DNA-1728 5696 binding, Nuclear protein, Transcription, Transcriptionregulation, Multigene family Contig706_RC CDNA FLJ32401 fis, 1729 5697clone SKMUS2000339 Contig726_RC FLJ13725 hypothetical proteinHypothetical protein 1730 5698 FLJ13725 Contig732_RC FTH1 transducer ofHypothetical protein 1731 5699 regulated cAMP response element- bindingprotein (CREB) 2 Contig7401_RC FLJ22756 PDZ domain Hypothetical protein1732 5700 containing 2 Contig75_RC RPS6KA2 ribosomal protein S6ATP-binding, Kinase, 1733 5701 kinase, 90 kDa, Serine/threonine-proteinkinase, polypeptide 2 Transferase, Repeat, Multigene family,Phosphorylation, Nuclear protein Contig773 FLJ20989 hypothetical proteinHypothetical protein 1734 5702 FLJ20989 Contig8210_RC DJ467N11.1dJ467N11.1 protein ATP-binding, Helicase, Hydrolase, 1735 5703Hypothetical protein Contig830_RC C1orf13 N-acetylneuraminate 1736 5704pyruvate lyase (dihydrodipicolinate synthase) Contig8371_RC Transcribed1737 5705 sequences Contig842_RC human T-cell Transcription regulation,DNA- 1738 5706 leukemia virus binding, Nuclear protein enhancer factorContig844_RC DKFZP566M1046 hypothetical protein Hypothetical protein1739 5707 DKFZp566M1046 Contig8547_RC Transcribed 1740 5708 sequencesContig883_RC KIAA1813 KIAA1813 protein Hypothetical protein 1741 5709Contig8885_RC HCS cytochrome c, Mitochondrion, Electron transport, 17425710 somatic Respiratory chain, Heme, Acetylation, Polymorphism,Apoptosis Contig8909_RC MGC45404 TAK1-binding Hypothetical protein 17435711 protein 3 Contig8956_RC FLJ13158 chromosome 6 open Hypotheticalprotein 1744 5712 reading frame 134 Contig8963_RC wi72b03.x1 1745 5713NCI_CGAP_Kid12 Homo sapiens cDNA clone IMAGE: 2398829 3′, mRNA sequence.Contig8980_RC DKFZP564B1162 hypothetical protein Hypothetical protein1746 5714 DKFZp564B1162 Contig9042_RC Transcribed 1747 5715 sequencesContig9059_RC FLJ12118 hypothetical protein Hypothetical protein 17485716 FLJ12118 Contig9136_RC CDNA FLJ43053 fis, 1749 5717 cloneBRTHA3006856 Contig9380_RC Transcribed 1750 5718 sequences Contig9514_RCTranscribed 1751 5719 sequences Contig9518_RC ZNF287 zinc finger proteinMetal-binding, Zinc, Zinc-finger, 1752 5720 287 Transcriptionregulation, Nuclear protein, DNA-binding, Repeat Contig964_RC MGC10433hypothetical protein Hypothetical protein 1753 5721 MGC10433Contig9714_RC MRNA for Hypothetical protein 1754 5722 hypotheticalprotein (ORF1), clone 00275 Contig973_RC MRPL45 mitochondrial Ribosomalprotein, Mitochondrion, 1755 5723 ribosomal protein Transit peptide L45Contig9810_RC KCNE1 potassium voltage- Transport, Ion transport, Ionic1756 5724 gated channel, lsk- channel, Voltage-gated channel, relatedfamily, Potassium channel, Potassium, member 1 Potassium transport,Transmembrane, Phosphorylation, Glycoprotein, Polymorphism, Diseasemutation, Long QT syndrome, Deafness Contig9965_RC DHODH dihydroorotatePyrimidine biosynthesis, 1757 5725 dehydrogenase Oxidoreductase,Flavoprotein, FAD, Transit peptide, Mitochondrion, 3D- structure D10040FACL2 acyl-CoA synthetase Ligase, Fatty acid metabolism, 1758 5726long-chain family Magnesium, Multigene family, member 1 Hypotheticalprotein D13642 SF3B3 splicing factor 3b, Spliceosome, mRNA processing,1759 5727 subunit 3, 130 kDa mRNA splicing, Nuclear protein,Hypothetical protein D16816 REG1B regenerating islet- Glycoprotein,Signal, Lectin, 1760 5728 derived 1 beta Pyrrolidone carboxylic acid(pancreatic stone protein, pancreatic thread protein) D21064 INPP5Epeptidase Hypothetical protein, Hydrolase, 1761 5729 (mitochondrialMetalloprotease, Mitochondrion, processing) alpha Transit peptide D25218RRS1 RRS1 ribosome Ribosome biogenesis, Nuclear 1762 5730 biogenesisregulator protein homolog (S. cerevisiae) D25328 PFKPphosphofructokinase, Kinase, Transferase, Glycolysis, 1763 5731 plateletRepeat, Allosteric enzyme, Phosphorylation, Magnesium, Multigene familyD26070 ITPR1 inositol 1,4,5- Receptor, Transmembrane, 1764 5732triphosphate Phosphorylation, Endoplasmic receptor, type 1 reticulum,Ionic channel, Ion transport, Calcium channel, Alternative splicing,Repeat D26362 BRD3 bromodomain Bromodomain, Repeat, Nuclear 1765 5733containing 3 protein D26488 KIAA0007 KIAA0007 protein Hypotheticalprotein, Repeat, WD 1766 5734 repeat D29954 KIAA0056 KIAA0056 proteinHypothetical protein 1767 5735 D29958 KIAA0116 KIAA0116 protein Exosome,Hydrolase, Nuclease, 1768 5736 Exonuclease, rRNA processing, Nuclearprotein, RNA-binding, Polymorphism, Hypothetical protein D31886 RAB3GAPRAB3 GTPase- Hypothetical protein 1769 5737 ACTIVATING PROTEIN D31887KIAA0062 solute carrier family Hypothetical protein 1770 5738 39 (zinctransporter), member 14 D38435 PMS2L1 postmeiotic Hypothetical protein,DNA repair, 1771 5739 segregation Anti-oncogene, Nuclear protein,increased 2-like 6 Polymorphism, Disease mutation, Hereditarynonpolyposis colorectal cancer, 3D-structure D38522 SYT11 Homo sapiensTransmembrane, Repeat, Synapse, 1772 5740 KIAA0080 mRNA, Hypotheticalprotein partial cds. D38549 CYFIP1 cytoplasmic FMR1 Hypothetical protein1773 5741 interacting protein 1 D42043 KIAA0084 raft-linking proteinHypothetical protein 1774 5742 D42084 METAP1 methionyl Hydrolase,Aminopeptidase, Cobalt 1775 5743 aminopeptidase 1 D43948 KIAA0097KIAA0097 gene Hypothetical protein, Repeat 1776 5744 product D43949KIAA0082 KIAA0082 Hypothetical protein 1777 5745 D50402 SLC11A1 solutecarrier family Transport, Iron transport, 1778 5746 11 (proton-coupledTransmembrane, Glycoprotein, divalent metal ion Macrophage, Polymorphismtransporters), member 1 D50911 GSA7 KIAA0121 gene Hypothetical protein1779 5747 product D50918 6-Sep septin 6 Cell division, GTP-binding,Coiled 1780 5748 coil, Alternative splicing D63487 KIAA0153 KIAA0153protein Hypothetical protein 1781 5749 D79998 KCTD2 potassium channelHypothetical protein 1782 5750 tetramerisation domain containing 2D80007 PDCD11 programmed cell Nuclear protein, rRNA processing, 17835751 death 11 Repeat, Polymorphism D80010 LPIN1 lipin 1 Nuclear protein,Polymorphism 1784 5752 D83781 NUP160 nucleoporin 160 kDa Nuclearprotein, Transport, 1785 5753 Alternative splicing, Hypothetical proteinD84294 TTC3 tetratricopeptide Repeat, TPR repeat, Zinc-finger, 1786 5754repeat domain 3 Alternative splicing, Polymorphism, Metal-binding D86964DOCK2 dedicator of Guanine-nucleotide releasing factor, 1787 5755cytokinesis 2 Membrane, Cytoskeleton, SH3 domain, Alternative splicing,Polymorphism D86973 GCN1L1 GCN1 general Hypothetical protein 1788 5756control of amino-acid synthesis 1-like 1 (yeast) D86976 HA-1 minor 17895757 histocompatibility antigen HA-1 D87442 NCSTN nicastrinTransmembrane, Glycoprotein, 1790 5758 Signal, Alternative splicingD87449 SLC35D1 solute carrier family Transport, Sugar transport, 17915759 35 (UDP-glucuronic Transmembrane, Endoplasmic acid/UDP-N- reticulumacetylgalactosamine dual transporter), member D1 D87453 MRPS27mitochondrial Hypothetical protein, Ribosomal 1792 5760 ribosomalprotein protein, Mitochondrion S27 D87466 KIAA0276 KIAA0276 proteinHypothetical protein 1793 5761 G26403 C9orf19 chromosome 9 openHypothetical protein 1794 5762 reading frame 19 J03077 PSAP prosaposin(variant Signal, Glycoprotein, Lysosome, 1795 5763 Gaucher diseaseSphingolipid metabolism, Repeat, and variant Gaucher disease, GM2-metachromatic gangliosidosis, Disease mutation, leukodystrophy)Metachromatic leukodystrophy, Alternative splicing, 3D-structure J03796EPB41 erythrocyte Structural protein, Alternative 1796 5764 membraneprotein splicing, Cytoskeleton, Actin-binding, band 4.1 Phosphorylation,Pyropoikilocytosis, (elliptocytosis 1, RH- Glycoprotein, Elliptocytosis,linked) Hereditary hemolytic anemia, Polymorphism, 3D-structure J04162FCGR3A Fc fragment of IgG, Receptor, IgG-binding protein, 1797 5765 lowaffinity IIIa, Transmembrane, Glycoprotein, receptor for (CD16) Signal,Immunoglobulin domain, Repeat, Multigene family, Polymorphism,GPI-anchor, 3D- structure, Lipoprotein J04178 HEXA hexosaminidase AHydrolase, Glycosidase, Lysosome, 1798 5766 (alpha polypeptide)GM2-gangliosidosis, Signal, Zymogen, Glycoprotein, Disease mutation,Polymorphism, 3D- structure K02276 MYC v-myc Proto-oncogene, Nuclearprotein, 1799 5767 myelocytomatosis DNA-binding, Phosphorylation, viraloncogene Transcription regulation, Activator, homolog (avian)Glycoprotein, Polymorphism, 3D- structure K02403 C4A complementComplement pathway, Plasma, 1800 5768 component 4A Glycoprotein,Sulfation, Signal, Inflammatory response, Polymorphism, Diseasemutation, Blood group antigen, Thioester bond L00635 FNTBfarnesyltransferase, Plasmid, Transferase, 1801 5769 CAAX box, betaPrenyltransferase, Repeat, Zinc L08246 MCL1 myeloid cell Apoptosis,Transmembrane, 1802 5770 leukemia sequence Differentiation, Alternativesplicing 1 (BCL2-related) L20688 ARHGDIB Rho GDP GTPase activation,3D-structure 1803 5771 dissociation inhibitor (GDI) beta L21961 IGL@Human Ig Immunoglobulin domain, 1804 5772 rearranged lambda-Hypothetical protein, chain mRNA, Immunoglobulin C region, 3D- subgroupVL3, V-J structure region, partial cds. L22005 CDC34 cell division cycle34 Ubl conjugation pathway, Ligase, 1805 5773 Multigene family,Hypothetical protein, Cell division L27943 CDA cytidine deaminaseHydrolase, Zinc 1806 5774 L35035 RPIA ribose 5-phosphate Isomerase 18075775 isomerase A (ribose 5-phosphate epimerase) L39061 TAF1B TATA boxbinding Hypothetical protein 1808 5776 protein (TBP)- associated factor,RNA polymerase I, B, 63 kDa L40027 GSK3A glycogen synthase Transferase,Serine/threonine- 1809 5777 kinase 3 alpha protein kinase, ATP-binding,Multigene family, Phosphorylation M12679 HLA-C major Glycoprotein,Signal, 1810 5778 histocompatibility Transmembrane, Hypotheticalcomplex, class I, C protein, MHC, MHC I, Polymorphism, 3D-structure,Alternative splicing M12758 HLA-C Human MHC class I Glycoprotein,Transmembrane 1811 5779 HLA-A cell surface antigen mRNA,(HLA-A2,-B7,-C), clone JY103. M17733 TMSB4X thymosin, beta 4, X-Actin-binding, Cytoskeleton, 1812 5780 linked Acetylation M26383 IL8interleukin 8 Cytokine, Chemotaxis, Inflammatory 1813 5781 response,Signal, Alternative splicing, 3D-structure M31212 MYL6 myosin, lightMyosin, Muscle protein, Acetylation, 1814 5782 polypeptide 6, alkali,Alternative splicing, Multigene family smooth muscle and non-muscleM31523 TCF3 transcription factor 3 Transcription regulation, DNA- 18155783 (E2A binding, Nuclear protein, Proto- immunoglobulin oncogene,Chromosomal enhancer binding translocation, Alternative splicing,factors E12/E47) Phosphorylation, 3D-structure M33552 LSP1lymphocyte-specific T-cell, Phosphorylation, 1816 5784 protein 1Polymorphism M34671 CD59 CD59 antigen p18-20 Antigen, Glycoprotein,GPI-anchor, 1817 5785 (antigen identified Signal, 3D-structure,Lipoprotein by monoclonal antibodies 16.3A5, EJ16, EJ30, EL32 and G344)M37712 CDC2L2 Homo sapiens Apoptosis, Transferase, 1818 5786 p58/GTAprotein Serine/threonine-protein kinase, kinase mRNA, ATP-binding, Cellcycle, complete cds. Phosphorylation, Alternative splicing, Alternativeinitiation M60721 HLX1 H2.0-like homeo box DNA-binding, Homeobox,Nuclear 1819 5787 1 (Drosophila) protein, Transcription regulationM63438 IGKC Immunoglobulin Hypothetical protein 1820 5788 kappa lightchain mRNA, partial cds M65292 HFL1 H factor Repeat, Glycoprotein,Sushi, Signal, 1821 5789 (complement)-like 1 Polymorphism M74782 IL3RAinterleukin 3 Receptor, Transmembrane, 1822 5790 receptor, alpha (lowGlycoprotein, Signal affinity) M83822 LRBA LPS-responsive Repeat, WDrepeat 1823 5791 vesicle trafficking, beach and anchor containing M90657TM4SF1 Human tumor Glycoprotein, Antigen, 1824 5792 antigen (L6) mRNA,Transmembrane complete cds. M91211 AGER advanced Immunoglobulin domain,1825 5793 glycosylation end Glycoprotein, Transmembrane,product-specific Repeat, Signal, Alternative splicing, receptorPolymorphism, Receptor M92439 LRPPRC leucine-rich PPR- Hypotheticalprotein, Repeat 1826 5794 motif containing M92642 COL16A1 collagen, typeXVI, Extracellular matrix, Connective 1827 5795 alpha 1 tissue,Collagen, Hydroxylation, Repeat, Signal M94362 LMNB2 Human lamin B2Intermediate filament, Coiled coil, 1828 5796 (LAMB2) mRNA, Nuclearprotein, Lipoprotein, partial cds. Prenylation, Phosphorylation,Hypothetical protein NM_000016 ACADM acyl-Coenzyme A Oxidoreductase,Flavoprotein, FAD, 1829 5797 dehydrogenase, C-4 Fatty acid metabolism,to C-12 straight Mitochondrion, Transit peptide, chain Disease mutation,3D-structure NM_000018 ACADVL acyl-Coenzyme A Oxidoreductase,Flavoprotein, FAD, 1830 5798 dehydrogenase, very Fatty acid metabolism,long chain Mitochondrion, Transit peptide, Alternative splicing, Diseasemutation, Polymorphism, Cardiomyopathy NM_000021 PSEN1 presenilin 1Transmembrane, Phosphorylation, 1831 5799 (Alzheimer disease Endoplasmicreticulum, Golgi stack, 3) Alzheimer's disease, Disease mutation,Polymorphism, Alternative splicing NM_000022 ADA adenosine Hydrolase,Nucleotide metabolism, 1832 5800 deaminase SCID, Hereditary hemolyticanemia, Disease mutation, Polymorphism NM_000026 ADSL adenylosuccinatePurine biosynthesis, Lyase, 1833 5801 lyase Alternative splicing,Disease mutation, Epilepsy NM_000030 AGXT alanine-glyoxylateAminotransferase, Transferase, 1834 5802 aminotransferase Pyridoxalphosphate, Peroxisome, (oxalosis I; Mitochondrion, Disease mutation,hyperoxaluria I; Polymorphism glycolicaciduria; serine-pyruvateaminotransferase) NM_000034 ALDOA aldolase A, fructose- Lyase, Schiffbase, Glycolysis, 1835 5803 bisphosphate Multigene family, 3D-structure,Disease mutation NM_000045 ARG1 arginase, liver Urea cycle, Argininemetabolism, 1836 5804 Hydrolase, Manganese, Disease mutation,Polymorphism NM_000056 BCKDHB branched chain keto Oxidoreductase,Mitochondrion, 1837 5805 acid dehydrogenase Transit peptide, Diseasemutation, E1, beta polypeptide Maple syrup urine disease, 3D- (maplesyrup urine structure disease) NM_000070 CAPN3 calpain 3, (p94)Hydrolase, Thiol protease, Calcium- 1838 5806 binding, Multigene family,Repeat, Disease mutation, Polymorphism, Alternative splicing NM_000073CD3G CD3G antigen, Immunoglobulin domain, T-cell, 1839 5807 gammapolypeptide Receptor, Transmembrane, (TiT3 complex) Glycoprotein, SignalNM_000074 TNFSF5 tumor necrosis factor Cytokine, Transmembrane, 18405808 (ligand) superfamily, Glycoprotein, Signal-anchor, member 5 (hyper-Antigen, Disease mutation, IgM syndrome) Polymorphism, 3D-structureNM_000081 CHS1 Chediak-Higashi Protein transport, Transport, Repeat,1841 5809 syndrome 1 WD repeat, Disease mutation, Alternative splicingNM_000082 CKN1 Cockayne syndrome Nuclear protein, Repeat, WD repeat,1842 5810 1 (classical) Transcription regulation, Polymorphism,Cockayne's syndrome, Deafness, Dwarfism NM_000095 COMP cartilageoligomeric Hypothetical protein, Glycoprotein, 1843 5811 matrix proteinCell adhesion, Calcium-binding, (pseudoachondroplasia, Repeat, EGF-likedomain, Signal, epiphyseal Disease mutation, Polymorphism dysplasia 1,multiple) NM_000099 CST3 cystatin C (amyloid Thiol protease inhibitor,Amyloid, 1844 5812 angiopathy and Signal, Disease mutation, cerebralPolymorphism, 3D-structure hemorrhage) NM_000100 CSTB cystatin B (stefinB) Thiol protease inhibitor, Nuclear 1845 5813 protein, Acetylation,Disease mutation, Epilepsy, 3D-structure NM_000101 CYBA cytochromeb-245, Oxidoreductase, NADP, Electron 1846 5814 alpha polypeptidetransport, Membrane, Heme, Polymorphism, Disease mutation, Chronicgranulomatous disease, Hypothetical protein NM_000116 TAZ tafazzinAlternative splicing, 1847 5815 (cardiomyopathy, Transmembrane, Diseasemutation dilated 3A (X-linked); endocardial fibroelastosis 2; Barthsyndrome) NM_000120 EPHX1 epoxide hydrolase 1, Hydrolase, Endoplasmicreticulum, 1848 5816 microsomal Detoxification, Transmembrane,(xenobiotic) Aromatic hydrocarbons catabolism, Microsome, PolymorphismNM_000121 EPOR erythropoietin Receptor, Transmembrane, 1849 5817receptor Glycoprotein, Signal, Phosphorylation, 3D-structure NM_000126ETFA electron-transfer- Electron transport, Flavoprotein, 1850 5818flavoprotein, alpha FAD, Mitochondrion, Transit peptide, polypeptide(glutaric Disease mutation, Glutaricaciduria, aciduria II) Polymorphism,3D-structure NM_000130 F5 coagulation factor V Blood coagulation,Glycoprotein, 1851 5819 (proaccelerin, labile Sulfation, Calcium,Signal, Zymogen, factor) Repeat, Polymorphism, Disease mutation,Thrombophilia, 3D- structure NM_000143 FH fumarate hydratase Lyase,Tricarboxylic acid cycle, 1852 5820 Mitochondrion, Transit peptide,Acetylation, Alternative initiation, Anti-oncogene, Disease mutationNM_000146 FTL ferritin, light Hypothetical protein, Iron storage, 18535821 polypeptide Metal-binding, Acetylation NM_000151 G6PC glucose-6-Glycogen biosynthesis, Hydrolase, 1854 5822 phosphatase, Transmembrane,Glycoprotein, catalytic (glycogen Endoplasmic reticulum, Glycogenstorage disease type storage disease, Disease mutation, I, von GierkePolymorphism disease) NM_000156 GAMT guanidinoacetate N- Transferase,Methyltransferase 1855 5823 methyltransferase NM_000157 GBA glucosidase,beta; Glycosidase, Hydrolase, Signal, 1856 5824 acid (includesHypothetical protein, Sphingolipid glucosylceramidase) metabolism,Glycoprotein, Lysosome, Membrane, Gaucher disease, Disease mutation,Polymorphism, Alternative initiation, Pharmaceutical NM_000175 GPIglucose phosphate Gluconeogenesis, Glycolysis, 1857 5825 isomeraseIsomerase, Growth factor, Cytokine, Disease mutation, 3D-structure,Hypothetical protein NM_000177 GSN gelsolin Cytoskeleton, Actin-binding,Repeat, 1858 5826 (amyloidosis, Finnish Calcium, Alternative initiation,type) Signal, Amyloid, Disease mutation, 3D-structure, Phosphorylation,Actin capping NM_000181 GUSB glucuronidase, beta Hydrolase, Glycosidase,Lysosome, 1859 5827 Glycoprotein, Signal, Mucopolysaccharidosis, Diseasemutation, 3D-structure, Alternative splicing, Polymorphism NM_000183HADHB hydroxyacyl- Fatty acid metabolism, Transferase, 1860 5828Coenzyme A Acyltransferase, Mitochondrion, dehydrogenase/3- Transitpeptide, Disease mutation, ketoacyl-Coenzyme Hypothetical protein Athiolase/enoyl- Coenzyme A hydratase (trifunctional protein), betasubunit NM_000186 HF1 H factor 1 Complement alternate pathway, 1861 5829(complement) Plasma, Glycoprotein, Repeat, Sushi, Signal, 3D-structure,Polymorphism, Alternative splicing NM_000206 IL2RG interleukin 2Receptor, Transmembrane, 1862 5830 receptor, gamma Glycoprotein, Signal,Disease (severe combined mutation, SCID, 3D-structure immunodeficiency)NM_000211 ITGB2 integrin, beta 2 Integrin, Cell adhesion, Receptor, 18635831 (antigen CD18 (p95), Transmembrane, Glycoprotein, lymphocytefunction- Repeat, Signal, Disease mutation, associated antigenPyrrolidone carboxylic acid, 3D- 1; macrophage structure antigen 1(mac-1) beta subunit) NM_000229 LCAT lecithin-cholesterol Cholesterolmetabolism, Lipid 1864 5832 acyltransferase metabolism, Transferase,Acyltransferase, Signal, Glycoprotein, Polymorphism, Disease mutationNM_000235 LIPA lipase A, lysosomal Hydrolase, Lipid degradation, 18655833 acid, cholesterol Glycoprotein, Signal, Lysosome, esterase (WolmanDisease mutation, Polymorphism disease) NM_000239 LYZ lysozyme (renalHydrolase, Glycosidase, 1866 5834 amyloidosis) Bacteriolytic enzyme,Signal, Amyloid, 3D-structure, Disease mutation, Polymorphism NM_000243MEFV Mediterranean fever Inflammatory response, Actin- 1867 5835binding, Metal-binding, Cytoskeleton, Microtubule, Nuclear protein,Zinc- finger, Zinc, Polymorphism, Disease mutation, Alternative splicingNM_000249 MLH1 mutL homolog 1, DNA repair, Nuclear protein, 1868 5836colon cancer, Disease mutation, Anti-oncogene, nonpolyposis type 2Polymorphism, Hereditary (E. coli) nonpolyposis colorectal cancerNM_000250 MPO myeloperoxidase Oxidoreductase, Peroxidase, Iron, 18695837 Heme, Calcium-binding, Glycoprotein, Signal, Oxidation, Lysosome,Alternative splicing, Polymorphism, Disease mutation, 3D-structureNM_000254 MTR 5- Transferase, Methyltransferase, 1870 5838methyltetrahydrofolate- Methionine biosynthesis, Vitamin homocysteineB12, Cobalt, Disease mutation, methyltransferase Polymorphism NM_000265NCF1 neutrophil cytosolic SH3 domain, Repeat, 1871 5839 factor 1 (47kDa, Polymorphism, Disease mutation, chronic Chronic granulomatousdisease, 3D- granulomatous structure disease, autosomal 1) NM_000269NME1 non-metastatic cells Transferase, Kinase, ATP-binding, 1872 5840 1,protein (NM23A) Nuclear protein, Anti-oncogene, expressed in Diseasemutation, 3D-structure NM_000270 NP nucleoside Hypothetical protein,Transferase, 1873 5841 phosphorylase Glycosyltransferase, Polymorphism,Disease mutation, 3D-structure NM_000285 PEPD peptidase D Collagendegradation, Hydrolase, 1874 5842 Dipeptidase, Metalloprotease,Manganese, Acetylation, Polymorphism, Disease mutation NM_000288 PEX7peroxisomal Repeat, WD repeat, Peroxisome, 1875 5843 biogenesis factor 7Transport, Protein transport, Rhizomelic chondrodysplasia punctata,Disease mutation, Polymorphism NM_000289 PFKM phosphofructokinase,Glycolysis, Kinase, Transferase, 1876 5844 muscle Repeat, Allostericenzyme, Phosphorylation, Magnesium, Multigene family, Alternativesplicing, Disease mutation, Glycogen storage disease NM_000291 PGK1phosphoglycerate Transferase, Kinase, Multigene 1877 5845 kinase 1family, Glycolysis, Acetylation, Disease mutation, Polymorphism,Hereditary hemolytic anemia NM_000295 SERPINA1 serine (or cysteine)Serpin, Serine protease inhibitor, 1878 5846 proteinase inhibitor,Glycoprotein, Plasma, clade A (alpha-1 Polymorphism, Acute phase,Signal, antiproteinase, 3D-structure, Disease mutation, antitrypsin),member 1 Protease inhibitor NM_000297 PKD2 polycystic kidney Ionicchannel, Glycoprotein, Coiled 1879 5847 disease 2 coil, Transmembrane,Calcium- (autosomal binding, Disease mutation, dominant) PolymorphismNM_000302 PLOD procollagen-lysine, Oxidoreductase, Dioxygenase, 18805848 2-oxoglutarate 5- Signal, Iron, Vitamin C, Glycoprotein,dioxygenase (lysine Endoplasmic reticulum, Membrane, hydroxylase,Ehlers- Polymorphism, Disease mutation, Danlos syndrome Ehlers-Danlossyndrome type VI) NM_000305 PON2 paraoxonase 2 Hydrolase, Glycoprotein,Signal, 1881 5849 Membrane, Multigene family, Polymorphism, Alternativesplicing NM_000307 POU3F4 POU domain, class Transcription regulation,Nuclear 1882 5850 3, transcription factor 4 protein, DNA-binding,Homeobox, Disease mutation, Deafness NM_000320 QDPR quinoidTetrahydrobiopterin biosynthesis, 1883 5851 dihydropteridineOxidoreductase, NADP, 3D- reductase structure, Polymorphism,Phenylketonuria, Disease mutation NM_000321 RB1 retinoblastoma 1Transcription regulation, DNA- 1884 5852 (including binding, Nuclearprotein, osteosarcoma) Phosphorylation, Anti-oncogene, Disease mutation,3D-structure NM_000327 ROM1 retinal outer Vision, Cell adhesion, 18855853 segment membrane Photoreceptor, Transmembrane, protein 1Polymorphism, Disease mutation, Retinitis pigmentosa NM_000376 VDRvitamin D (1,25- Receptor, Transcription regulation, 1886 5854dihydroxyvitamin D3) DNA-binding, Nuclear protein, Zinc- receptorfinger, Phosphorylation, Disease mutation, 3D-structure NM_000377 WASWiskott-Aldrich Repeat, Disease mutation, 1887 5855 syndrome (eczema-Phosphorylation, 3D-structure thrombocytopenia) NM_000380 XPA xerodermaDNA repair, DNA-binding, Zinc- 1888 5856 pigmentosum, finger, Nuclearprotein, Xeroderma complementation pigmentosum, Disease mutation, groupA Polymorphism, 3D-structure NM_000386 BLMH bleomycin hydrolaseHydrolase, Thiol protease, 1889 5857 Polymorphism, 3D-structure,Hypothetical protein NM_000392 ABCC2 ATP-binding ATP-binding,Glycoprotein, 1890 5858 cassette, sub-family Transmembrane, Transport,Repeat, C (CFTR/MRP), Disease mutation, Polymorphism member 2 NM_000394CRYAA crystallin, alpha A Eye lens protein, Acetylation, 1891 5859Glycoprotein, Disease mutation, Vision NM_000397 CYBB cytochrome b-245,Oxidoreductase, NADP, Electron 1892 5860 beta polypeptide transport,Transmembrane, FAD, (chronic Heme, Glycoprotein, Voltage-gatedgranulomatous channel, Ionic channel, Disease disease) mutation, Chronicgranulomatous disease NM_000399 EGR2 early growth Transcriptionregulation, Activator, 1893 5861 response 2 (Krox-20 DNA-binding,Nuclear protein, homolog, Repeat, Zinc-finger, Metal-binding,Drosophila) Alternative splicing, Disease mutation, Charcot-Marie-Toothdisease, Dejerine-Sottas syndrome NM_000401 EXT2 exostoses (multiple) 2Transferase, Glycosyltransferase, 1894 5862 Endoplasmic reticulum, Golgistack, Transmembrane, Signal-anchor, Glycoprotein, Anti-oncogene,Disease mutation, Hereditary multiple exostoses, Alternative splicingNM_000402 G6PD glucose-6-phosphate Oxidoreductase, NADP, Glucose 18955863 dehydrogenase metabolism, Disease mutation, Polymorphism,Hereditary hemolytic anemia, Alternative splicing, Acetylation NM_000404GLB1 galactosidase, beta 1 Hydrolase, Glycosidase, Lysosome, 1896 5864Signal, Alternative splicing, Glycoprotein, Polymorphism, Diseasemutation NM_000405 GM2A GM2 ganglioside Signal, Glycoprotein, Lysosome,1897 5865 activator protein Sphingolipid metabolism, GM2-gangliosidosis, Disease mutation, Polymorphism, 3D-structure NM_000407GP1BB glycoprotein Ib Hypothetical protein, Cell division, 1898 5866(platelet), beta GTP-binding, Coiled coil, Platelet, polypeptideTransmembrane, Glycoprotein, Hemostasis, Blood coagulation, Signal,Phosphorylation, Cell adhesion, Leucine-rich repeat NM_000418 IL4Rinterleukin 4 receptor Receptor, Transmembrane, 1899 5867 Glycoprotein,Signal, Disease mutation, Polymorphism, 3D- structure NM_000425 L1CAM L1cell adhesion Neurogenesis, Cell adhesion, 1900 5868 moleculeDevelopmental protein, (hydrocephalus, Glycoprotein, Transmembrane,stenosis of aqueduct Repeat, Antigen, Immunoglobulin of Sylvius 1, MASAdomain, Signal, Disease mutation, (mental retardation, Alternativesplicing aphasia, shuffling gait and adducted thumbs) syndrome, spasticparaplegia 1) NM_000433 NCF2 neutrophil cytosolic SH3 domain, Repeat,TPR repeat, 1901 5869 factor 2 (65 kDa, Chronic granulomatous disease,chronic Disease mutation, 3D-structure granulomatous disease, autosomal2) NM_000434 NEU1 sialidase 1 Hydrolase, Glycosidase, Signal, 1902 5870(lysosomal sialidase) Repeat, Glycoprotein, Disease mutation,Polymorphism, Phosphorylation NM_000436 OXCT 3-oxoacid CoAMitochondrion, Transferase, Transit 1903 5871 transferase peptide,Disease mutation, Polymorphism NM_000445 PLEC1 plectin 1, Coiled coil,Repeat, Structural 1904 5872 intermediate filament protein,Cytoskeleton, Actin-binding, binding protein Phosphorylation,Alternative splicing, 500 kDa Epidermolysis bullosa, Disease mutationNM_000454 SOD1 superoxide Antioxidant, Oxidoreductase, Metal- 1905 5873dismutase 1, soluble binding, Copper, Zinc, Acetylation, (amyotrophiclateral 3D-structure, Amyotrophic lateral sclerosis 1 (adult))sclerosis, Disease mutation NM_000456 SUOX sulfite oxidaseOxidoreductase, Mitochondrion, 1906 5874 Heme, Molybdenum, Transitpeptide, Disease mutation, 3D-structure NM_000462 UBE3A ubiquitinprotein Ligase, Nuclear protein, Ubl 1907 5875 ligase E3A (humanconjugation pathway, Alternative papilloma virus E6- splicing, Diseasemutation, associated protein, Polymorphism, 3D-structure, AngelmanHypothetical protein syndrome) NM_000476 AK1 adenylate kinase 1Transferase, Kinase, ATP-binding, 1908 5876 Acetylation, Diseasemutation NM_000480 AMPD3 adenosine Hydrolase, Nucleotide metabolism,1909 5877 monophosphate Multigene family, Polymorphism, deaminase(isoform Alternative splicing E) NM_000481 AMT aminomethyltransferaseHypothetical protein, Transferase, 1910 5878 (glycine Aminotransferase,Mitochondrion, cleavage system Transit peptide, Disease mutation proteinT) NM_000487 ARSA arylsulfatase A Hydrolase, Signal, Glycoprotein, 19115879 Lysosome, Disease mutation, Metachromatic leukodystrophy,Sphingolipid metabolism, Polymorphism, 3D-structure NM_000497 CYP11B1cytochrome P450, Steroidogenesis, Electron transport, 1912 5880 family11, subfamily Steroid metabolism, Oxidoreductase, B, polypeptide 1Monooxygenase, Mitochondrion, Membrane, Heme, Transit peptide,Polymorphism, Disease mutation NM_000502 EPX eosinophil Oxidoreductase,Peroxidase, Iron, 1913 5881 peroxidase Heme, Glycoprotein, Signal,Disease mutation NM_000507 FBP1 fructose-1,6- Hydrolase, Carbohydrate1914 5882 bisphosphatase 1 metabolism, Gluconeogenesis, Zinc, Allostericenzyme, Disease mutation, Polymorphism, 3D-structure, Hypotheticalprotein NM_000512 GALNS galactosamine (N- Hypothetical protein 1915 5883acetyl)-6-sulfate sulfatase (Morquio syndrome, mucopolysaccharidosistype IVA) NM_000517 HBA2 hemoglobin, alpha 2 Heme, Oxygen transport,Transport, 1916 5884 Erythrocyte, Disease mutation, Polymorphism,Acetylation, 3D- structure NM_000525 KCNJ11 potassium inwardly- Ionicchannel, Ion transport, Voltage- 1917 5885 rectifying channel, gatedchannel, Transmembrane, subfamily J, member Potassium transport,Polymorphism, 11 Disease mutation, Diabetes mellitus NM_000528 MAN2B1mannosidase, alpha, Glycosidase, Hydrolase, 1918 5886 class 2B, member 1Glycoprotein, Lysosome, Zymogen, Signal, Disease mutation, PolymorphismNM_000532 PCCB propionyl Coenzyme Hypothetical protein, Mitochondrion,1919 5887 A carboxylase, beta Transit peptide, Ligase, Diseasepolypeptide mutation NM_000542 SFTPB surfactant, Surface film, Gaseousexchange, 1920 5888 pulmonary- Glycoprotein, Repeat, associated proteinB Polymorphism, 3D-structure NM_000558 HBA1 hemoglobin, alpha 2 Heme,Oxygen transport, Transport, 1921 5889 Erythrocyte, Disease mutation,Polymorphism, Acetylation, 3D- structure NM_000565 IL6R interleukin 6receptor Receptor, Transmembrane, 1922 5890 Glycoprotein, Immunoglobulindomain, Repeat, Alternative splicing, Signal, 3D-structure NM_000569FCGR3A Fc fragment of IgG, IgG-binding protein, Receptor, 1923 5891 lowaffinity IIIa, Transmembrane, Glycoprotein, receptor for (CD16) Signal,Immunoglobulin domain, Repeat, Multigene family, Polymorphism,GPI-anchor, 3D- structure, Lipoprotein NM_000573 CR1 complementComplement pathway, Glycoprotein, 1924 5892 component (3b/4b)Transmembrane, Repeat, Signal, receptor 1, including Receptor, Sushi,Blood group Knops blood group antigen, Polymorphism, Pyrrolidone systemcarboxylic acid, 3D-structure NM_000578 SLC11A1 solute carrier familyTransport, Iron transport, 1925 5893 11 (proton-coupled Transmembrane,Glycoprotein, divalent metal ion Macrophage, Polymorphism transporters),member 1 NM_000581 GPX1 glutathione Oxidoreductase, Peroxidase, 19265894 peroxidase 1 Selenium, Selenocysteine, Erythrocyte, Polymorphism,Hypothetical protein NM_000584 IL8 interleukin 8 Cytokine, Chemotaxis,Inflammatory 1927 5895 response, Signal, Alternative splicing,3D-structure NM_000591 CD14 CD14 antigen Immune response, Inflammatory1928 5896 response, Signal, GPI-anchor, Repeat, Leucine-rich repeat,Glycoprotein, Antigen, Lipoprotein NM_000607 ORM1 orosomucoid 1Glycoprotein, Plasma, Acute phase, 1929 5897 Signal, Lipocalin,Polymorphism, Multigene family, Pyrrolidone carboxylic acid NM_000608ORM2 orosomucoid 1 Glycoprotein, Plasma, Acute phase, 1930 5898 Signal,Lipocalin, Multigene family, Polymorphism, Pyrrolidone carboxylic acidNM_000631 NCF4 neutrophil cytosolic SH3 domain, Alternative splicing,1931 5899 factor 4, 40 kDa 3D-structure NM_000632 ITGAM integrin, alphaM Integrin, Cell adhesion, Receptor, 1932 5900 (complement Glycoprotein,Transmembrane, component receptor Signal, 3D-structure, Repeat, 3,alpha; also known Magnesium, Calcium as CD11b (p170), macrophage antigenalpha polypeptide) NM_000633 BCL2 B-cell Proto-oncogene, Apoptosis, 19335901 CLL/lymphoma 2 Alternative splicing, Transmembrane, Mitochondrion,Phosphorylation, Chromosomal translocation, Polymorphism, Diseasemutation, 3D-structure NM_000634 IL8RA interleukin 8 G-protein coupledreceptor, 1934 5902 receptor, alpha Transmembrane, Glycoprotein,Chemotaxis, Polymorphism, 3D- structure, Receptor NM_000651 CR1complement Complement pathway, Glycoprotein, 1935 5903 component (3b/4b)Transmembrane, Repeat, Signal, receptor 1, including Receptor, Sushi,Blood group Knops blood group antigen, Polymorphism, Pyrrolidone systemcarboxylic acid, 3D-structure NM_000655 SELL selectin L EGF-like domain,Cell adhesion, 1936 5904 (lymphocyte Transmembrane, Glycoprotein,adhesion molecule Lectin, Selectin, Signal, Sushi, 1) Repeat,3D-structure NM_000671 ADH5 alcohol Oxidoreductase, Zinc, Metal-binding,1937 5905 dehydrogenase 5 NAD, Multigene family, Acetylation, (classIII), chi 3D-structure polypeptide NM_000675 ADORA2A adenosine A2aG-protein coupled receptor, 1938 5906 receptor Transmembrane,Glycoprotein, 3D- structure, Polymorphism NM_000688 ALAS1aminolevulinate, Heme biosynthesis, Transferase, 1939 5907 delta-,synthase 1 Acyltransferase, Mitochondrion, Transit peptide, Pyridoxalphosphate, Multigene family NM_000690 ALDH2 aldehyde Oxidoreductase,NAD, 1940 5908 dehydrogenase 2 Mitochondrion, Transit peptide, familyPolymorphism, 3D-structure (mitochondrial) NM_000694 ALDH3B1 aldehydeOxidoreductase, NAD 1941 5909 dehydrogenase 3 family, member B1NM_000698 ALOX5 arachidonate 5- Oxidoreductase, Dioxygenase, Iron, 19425910 lipoxygenase Leukotriene biosynthesis, Calcium NM_000701 ATP1A1ATPase, Na+/K+ Hydrolase, Sodium/potassium 1943 5911 transporting, alpha1 transport, Transmembrane, polypeptide Phosphorylation, Magnesium,Metal- binding, ATP-binding, Multigene family, Alternative splicingNM_000712 BLVRA biliverdin reductase A Oxidoreductase, NAD, NADP, Zinc,1944 5912 Polymorphism NM_000714 BZRP benzodiazapine Mitochondrion,Receptor, 1945 5913 receptor (peripheral) Transmembrane, PolymorphismNM_000717 CA4 carbonic anhydrase GPI-anchor, Membrane, Lyase, Zinc, 19465914 IV Signal, 3D-structure, Lipoprotein NM_000718 CACNA1B calciumchannel, Ionic channel, Transmembrane, Ion 1947 5915 voltage-dependent,transport, Voltage-gated channel, L type, alpha 1B Calcium channel,Glycoprotein, subunit Repeat, Multigene family, Calcium- binding,Phosphorylation, ATP- binding, Alternative splicing NM_000732 CD3D CD3Dantigen, delta Immunoglobulin domain, T-cell, 1948 5916 polypeptide(TiT3 Receptor, Transmembrane, complex) Glycoprotein, Signal NM_000734CD3Z CD3Z antigen, zeta T-cell, Receptor, Transmembrane, 1949 5917polypeptide (TiT3 Signal, Repeat, Alternative splicing, complex)Phosphorylation, 3D-structure NM_000748 CHRNB2 cholinergic receptor,Postsynaptic membrane, Ionic 1950 5918 nicotinic, beta channel,Glycoprotein, Signal, polypeptide 2 Transmembrane, Multigene family,(neuronal) Disease mutation, Epilepsy NM_000749 CHRNB3 cholinergicreceptor, Postsynaptic membrane, Ionic 1951 5919 nicotinic, betachannel, Glycoprotein, Signal, polypeptide 3 Transmembrane, Multigenefamily NM_000752 LTB4R leukotriene B4 Apoptosis, 3D-structure, RNA- 19525920 receptor 2 binding, Repeat, G-protein coupled receptor,Transmembrane, Glycoprotein NM_000757 CSF1 colony stimulating Cytokine,Growth factor, 1953 5921 factor 1 Glycoprotein, Proteoglycan,(macrophage) Transmembrane, Signal, Alternative splicing, 3D-structureNM_000760 CSF3R colony stimulating Cell adhesion, Receptor, Repeat, 19545922 factor 3 receptor Signal, Transmembrane, (granulocyte)Immunoglobulin domain, Glycoprotein, Alternative splicing, Polymorphism,3D-structure NM_000778 CYP4A11 cytochrome P450, Heme, Monooxygenase,1955 5923 family 4, subfamily Oxidoreductase, Electron transport, A,polypeptide 11 Membrane, Microsome, Endoplasmic reticulum, PolymorphismNM_000801 FKBP1A FK506 binding Isomerase, Rotamase, 3D-structure 19565924 protein 1A, 12 kDa NM_000804 FOLR3 folate receptor 3 Receptor,Glycoprotein, Signal, 1957 5925 (gamma) Folate-binding, Multigenefamily, Alternative splicing NM_000819 GART phosphoribosylglycinMultifunctional enzyme, Purine 1958 5926 amide biosynthesis, Ligase,Transferase, formyltransferase, Alternative splicing, Polymorphismphosphoribosylglycin amide synthetase, phosphoribosylaminoimidazolesynthetase NM_000846 GSTA2 glutathione S- Transferase, Multigene family,1959 5927 transferase A2 Polymorphism, 3D-structure NM_000856 GUCY1A3guanylate cyclase 1, Lyase, cGMP biosynthesis, 1960 5928 soluble, alpha3 Multigene family NM_000857 GUCY1B3 guanylate cyclase 1, Lyase, cGMPbiosynthesis, 1961 5929 soluble, beta 3 Alternative splicing NM_000871HTR6 5-hydroxytryptamine G-protein coupled receptor, 1962 5930(serotonin) receptor 6 Transmembrane, Glycoprotein, Multigene familyNM_000876 IGF2R insulin-like growth Transmembrane, Transport, 1963 5931factor 2 receptor Glycoprotein, Repeat, Receptor, Lysosome, Signal,Polymorphism, 3D-structure NM_000877 IL1R1 interleukin 1 Receptor,Repeat, Signal, 1964 5932 receptor, type I Transmembrane, Immunoglobulindomain, Glycoprotein, Phosphorylation, 3D-structure NM_000878 IL2RBinterleukin 2 Receptor, Transmembrane, 1965 5933 receptor, betaGlycoprotein, Signal, 3D-structure NM_000883 IMPDH1 IMP (inosineOxidoreductase, NAD, GMP 1966 5934 monophosphate) biosynthesis, Purinebiosynthesis, dehydrogenase 1 Multigene family, Repeat, CBS domain,Alternative splicing, Vision, Retinitis pigmentosa, Disease mutationNM_000895 LTA4H leukotriene A4 Multifunctional enzyme, Hydrolase, 19675935 hydrolase Leukotriene biosynthesis, Metalloprotease, Metal-binding,Zinc, 3D-structure NM_000903 NQO1 NAD(P)H Oxidoreductase, NAD, NADP,1968 5936 dehydrogenase, Flavoprotein, FAD, Multigene family, quinone 1Polymorphism, 3D-structure NM_000904 NQO2 NAD(P)H Oxidoreductase,Flavoprotein, FAD, 1969 5937 dehydrogenase, Multigene family, Zinc,3D-structure quinone 2 NM_000918 P4HB procollagen-proline, Redox-activecenter, Isomerase, 1970 5938 2-oxoglutarate 4- Endoplasmic reticulum,Repeat, dioxygenase (proline Signal, 3D-structure, Hypothetical4-hydroxylase), beta protein polypeptide (protein disulfide isomerase;thyroid hormone binding protein p55) NM_000952 PTAFR platelet-activatingG-protein coupled receptor, 1971 5939 factor receptor Transmembrane,Glycoprotein, Chemotaxis, Polymorphism, Hypothetical protein NM_000954PTGDS prostaglandin D2 Isomerase, Prostaglandin 1972 5940 synthase 21kDa biosynthesis, Transport, (brain) Glycoprotein, Signal, Membrane,Lipocalin, Polymorphism NM_000963 PTGS2 prostaglandin- Oxidoreductase,Dioxygenase, 1973 5941 endoperoxide Peroxidase, Glycoprotein, synthase 2Prostaglandin biosynthesis, Heme, (prostaglandin G/H Iron, Signal,Membrane, synthase and Polymorphism cyclooxygenase) NM_000966 RARGretinoic acid Receptor, Transcription regulation, 1974 5942 receptor,gamma DNA-binding, Nuclear protein, Zinc- finger, Multigene family,Alternative splicing, 3D-structure NM_000969 RPL5 ribosomal protein L5Ribosomal protein, rRNA-binding, 1975 5943 Hydrolase, Metalloprotease,Aminopeptidase, Zinc, Nuclear protein NM_000985 RPL17 ribosomal proteinHypothetical protein, Ribosomal 1976 5944 L17 protein NM_000992 RPL29ribosomal protein Methylation, Ribosomal protein, 1977 5945 L29 Repeat,Heparin-binding NM_000995 RPL34 ribosomal protein Ribosomal protein 19785946 L34 NM_001006 RPS3A ribosomal protein Ribosomal protein 1979 5947S3A NM_001017 RPS13 ribosomal protein Ribosomal protein 1980 5948 S13NM_001048 SST somatostatin Cleavage on pair of basic residues, 1981 5949Hormone, Signal, Pharmaceutical NM_001051 SSTR3 somatostatin G-proteincoupled receptor, 1982 5950 receptor 3 Transmembrane, Glycoprotein,Multigene family, Polymorphism NM_001052 SSTR4 somatostatin G-proteincoupled receptor, 1983 5951 receptor 4 Transmembrane, Glycoprotein,Multigene family, Lipoprotein, Palmitate, Phosphorylation, PolymorphismNM_001054 SULT1A2 sulfotransferase Transferase, Steroid metabolism, 19845952 family, cytosolic, 1A, Polymorphism phenol-preferring, member 2NM_001055 SULT1A1 sulfotransferase Transferase, Catecholamine 1985 5953family, cytosolic, 1A, metabolism, Steroid metabolism,phenol-preferring, Polymorphism member 1 NM_001060 TBXA2R thromboxane A2G-protein coupled receptor, 1986 5954 receptor Transmembrane,Glycoprotein, Disease mutation, Alternative splicing, Polymorphism, 3D-structure, Hypothetical protein, Metal-binding, Nuclear protein, Zinc,Zinc-finger NM_001062 TCN1 transcobalamin I Transport, Cobalt transport,1987 5955 (vitamin B12 binding Glycoprotein, Signal protein, R binderfamily) NM_001064 TKT transketolase Transferase, Thiamine 1988 5956(Wernicke-Korsakoff pyrophosphate, Calcium-binding syndrome) NM_001065TNFRSF1A tumor necrosis factor Receptor, Apoptosis, 1989 5957 receptorsuperfamily, Transmembrane, Glycoprotein, member 1A Repeat, Signal,Disease mutation, Polymorphism, 3D-structure NM_001066 TNFRSF1B tumornecrosis factor Receptor, Apoptosis, 1990 5958 receptor superfamily,Transmembrane, Glycoprotein, member 1B Repeat, Signal, Phosphorylation,Pharmaceutical, Polymorphism, 3D- structure NM_001082 CYP4F2 cytochromeP450, Heme, Monooxygenase, 1991 5959 family 4, subfamily Oxidoreductase,Electron transport, F, polypeptide 2 Membrane, Microsome, Endoplasmicreticulum, Polymorphism, NADP NM_001087 AAMP angio-associated, Repeat,WD repeat 1992 5960 migratory cell protein NM_001089 ABCA3 ATP-bindingATP-binding, Transport, 1993 5961 cassette, sub-family Transmembrane A(ABC1), member 3 NM_001090 ABCF1 ATP-binding ATP-binding 1994 5962cassette, sub-family F (GCN20), member 1 NM_001091 ABP1 amiloridebinding Signal, Glycoprotein, 1995 5963 protein 1 (amine Oxidoreductase,Copper, Heparin- oxidase (copper- binding, TPQ, Alternative splicing,containing)) Polymorphism, Metal-binding NM_001099 ACPP acidphosphatase, Hydrolase, Glycoprotein, Signal, 3D- 1996 5964 prostatestructure NM_001101 ACTB actin, beta Hypothetical protein, Structural1997 5965 protein, Multigene family, Methylation, Acetylation,Cytoskeleton, 3D-structure NM_001102 ACTN1 actinin, alpha 1Cytoskeleton, Actin-binding, 1998 5966 Calcium-binding, Repeat,Multigene family, Phosphorylation NM_001105 ACVR1 activin A receptor,Receptor, Transferase, 1999 5967 type I Serine/threonine-protein kinase,ATP-binding, Transmembrane, Glycoprotein, Signal NM_001107 ACYP1acylphosphatase 1, Hydrolase, Acetylation, Multigene 2000 5968erythrocyte family (common) type NM_001109 ADAM8 a disintegrin andHydrolase, Metalloprotease, Zinc, 2001 5969 metalloproteinase Signal,Glycoprotein, domain 8 Transmembrane, Antigen, EGF-like domain NM_001120TETRAN tetracycline Transmembrane 2002 5970 transporter-like proteinNM_001129 AEBP1 AE binding protein 1 Carboxypeptidase 2003 5971NM_001140 ALOX15 arachidonate 15- Oxidoreductase, Dioxygenase, Iron,2004 5972 lipoxygenase Leukotriene biosynthesis NM_001150 ANPEP alanyl(membrane) Angiogenesis, Hydrolase, 2005 5973 aminopeptidaseAminopeptidase, Metalloprotease, (aminopeptidase N, Zinc, Signal-anchor,aminopeptidase M, Transmembrane, Glycoprotein, microsomal Sulfation,Polymorphism aminopeptidase, CD13, p150) NM_001152 SLC25A5 solutecarrier family Mitochondrion, Inner membrane, 2006 5974 25(mitochondrial Repeat, Transmembrane, Transport, carrier; adenineMultigene family nucleotide translocator), member 5 NM_001153 ANXA4annexin A4 Annexin, Calcium/phospholipid- 2007 5975 binding, RepeatNM_001155 ANXA6 annexin A6 Annexin, Calcium/phospholipid- 2008 5976binding, Repeat, Acetylation, Phosphorylation, 3D-structure NM_001157ANXA11 annexin A11 Annexin, Calcium/phospholipid- 2009 5977 binding,Repeat, Polymorphism NM_001172 ARG2 arginase, type II Urea cycle,Arginine metabolism, 2010 5978 Hydrolase, Manganese, Transit peptide,Mitochondrion, Receptor, Transmembrane, Transport, Protein transport,Coiled coil, Alternative splicing NM_001175 ARHGDIB Rho GDP GTPaseactivation, 3D-structure 2011 5979 dissociation inhibitor (GDI) betaNM_001181 ASGR2 asialoglycoprotein Lectin, Glycoprotein, Receptor, 20125980 receptor 2 Endocytosis, Transmembrane, Calcium, Signal-anchor,Phosphorylation, Alternative splicing NM_001182 ALDH7A1 aldehydeOxidoreductase, NAD 2013 5981 dehydrogenase 7 family, member A1NM_001183 ATP6IP1 ATPase, H+ Hypothetical protein, ATP synthesis, 20145982 transporting, Hydrogen ion transport, Hydrolase, lysosomalaccessory ATP-binding, Transmembrane, protein 1 Glycoprotein, SignalNM_001184 ATR ataxia telangiectasia Kinase, Transferase 2015 5983 andRad3 related NM_001196 BID BH3 interacting Apoptosis, 3D-structure 20165984 domain death agonist NM_001199 BMP1 bone morphogenetic Growthfactor, Cytokine, Repeat, 2017 5985 protein 1 Osteogenesis,Chondrogenesis, Hydrolase, Metalloprotease, EGF- like domain, Zinc,Calcium, Signal, Glycoprotein, Zymogen, Alternative splicing, CollagenNM_001206 BTEB1 basic transcription Transcription regulation, DNA- 20185986 element binding binding, Nuclear protein, Repeat, protein 1Zinc-finger, Metal-binding NM_001207 BTF3 basic transcriptionTranscription regulation, Nuclear 2019 5987 factor 3 protein,Alternative splicing NM_001208 BTF3L1 basic transcription Transcriptionregulation, Nuclear 2020 5988 factor 3, like 1 protein NM_001212 C1QBPcomplement Mitochondrion, Transit peptide, 3D- 2021 5989 component 1, qstructure, Hypothetical protein subcomponent binding protein NM_001222CAMK2G calcium/calmodulin- Alternative splicing 2022 5990 dependentprotein kinase (CaM kinase) II gamma NM_001237 CCNA2 cyclin A2 Cyclin,Cell cycle, Cell division, 2023 5991 Mitosis, 3D-structure NM_001252TNFSF7 tumor necrosis factor Cytokine, Transmembrane, 2024 5992 (ligand)superfamily, Glycoprotein, Signal-anchor, Antigen member 7 NM_001256CDC27 cell division cycle 27 Repeat, TPR repeat, Nuclear 2025 5993protein, Polymorphism NM_001259 CDK6 cyclin-dependent Transferase,Serine/threonine- 2026 5994 kinase 6 protein kinase, ATP-binding, Cellcycle, Cell division, Phosphorylation, 3D-structure NM_001266 CES1carboxylesterase 1 Glycoprotein, Hydrolase, Serine 2027 5995(monocyte/macrophage esterase, Endoplasmic reticulum, serine esteraseSignal, Multigene family, 1) Polymorphism, Hypothetical proteinNM_001276 CHI3L1 chitinase 3-like 1 Glycoprotein, Signal, 3D-structure2028 5996 (cartilage glycoprotein-39) NM_001282 AP2B1 adaptor-relatedHypothetical protein, Coated pits, 2029 5997 protein complex 2,3D-structure beta 1 subunit NM_001284 AP3S1 adaptor-related Golgi stack,Protein transport, 2030 5998 protein complex 3, Transport sigma 1subunit NM_001286 CLCN6 chloride channel 6 Ionic channel, Ion transport,Chloride 2031 5999 channel, Chloride, Voltage-gated channel,Transmembrane, CBS domain, Repeat, Alternative splicing NM_001288 CLIC1chloride intracellular Ionic channel, Ion transport, Chloride 2032 6000channel 1 channel, Chloride, Voltage-gated channel, Nuclear protein, 3D-structure NM_001292 CLK3 CDC-like kinase 3 Transferase,Serine/threonine- 2033 6001 protein kinase, ATP-binding,Tyrosine-protein kinase, Phosphorylation, Nuclear protein, Alternativesplicing NM_001293 CLNS1A chloride channel, Nuclear protein,Polymorphism 2034 6002 nucleotide-sensitive, 1A NM_001294 CLPTM1 cleftlip and palate Transmembrane 2035 6003 associated transmembrane protein1 NM_001305 CLDN4 claudin 4 Tight junction, Transmembrane, 2036 6004Williams-Beuren syndrome NM_001313 CRMP1 collapsin response Repeat, WDrepeat 2037 6005 mediator protein 1 NM_001315 MAPK14 mitogen-activatedATP-binding, Kinase, Transferase, 2038 6006 protein kinase 14Serine/threonine-protein kinase, Phosphorylation, Alternative splicing,3D-structure NM_001317 CSH1 chorionic Chorion, Hormone, Placenta, 20396007 somatomammotropin Multigene family, Signal hormone 1 (placentallactogen) NM_001325 CSTF2 cleavage stimulation RNA-binding, Repeat, 20406008 factor, 3′ pre-RNA, Phosphorylation, Nuclear protein subunit 2, 64kDa NM_001331 CTNND1 catenin (cadherin- Cytoskeleton, Structuralprotein, 2041 6009 associated protein), Phosphorylation, Repeat, Celldelta 1 adhesion, Coiled coil, Nuclear protein, Alternative splicingNM_001338 CXADR coxsackie virus and Immunoglobulin domain, Receptor,2042 6010 adenovirus receptor Transmembrane, Glycoprotein, Signal,Repeat, 3D-structure NM_001346 DGKG diacylglycerol Transferase, Kinase,Calcium- 2043 6011 kinase, gamma binding, Phorbol-ester binding, 90 kDaRepeat, Multigene family, Alternative splicing NM_001357 DDX9 DEAH(Asp-Glu-Ala- Helicase, RNA-binding, DNA- 2044 6012 His) box polypeptide9 binding, Repeat, Nuclear protein, ATP-binding NM_001358 DDX15 DEAH(Asp-Glu-Ala- mRNA processing, mRNA splicing, 2045 6013 His) boxpolypeptide Helicase, ATP-binding, Nuclear 15 protein NM_001363 DKC1dyskeratosis Telomere, RNA-binding, Nuclear 2046 6014 congenita 1,protein, Disease mutation dyskerin NM_001381 DOK1 docking protein 1,Phosphorylation, Alternative splicing 2047 6015 62 kDa (downstream oftyrosine kinase 1) NM_001383 DPH2L1 diptheria toxin 2048 6016 resistanceprotein required for diphthamide biosynthesis-like 1 (S. cerevisiae)NM_001388 DRG2 developmentally GTP-binding 2049 6017 regulated GTPbinding protein 2 NM_001406 EFNB3 ephrin-B3 Developmental protein, 20506018 Neurogenesis, Transmembrane, Glycoprotein, Signal, PolymorphismNM_001415 EIF2S3 eukaryotic Initiation factor, Protein biosynthesis,2051 6019 translation initiation GTP-binding, Polymorphism factor 2,subunit 3 gamma, 52 kDa NM_001419 ELAVL1 ELAV (embryonic RNA-binding,Repeat 2052 6020 lethal, abnormal vision, Drosophila)- like 1 (Huantigen R) NM_001421 ELF4 E74-like factor 4 (ets 2053 6021 domaintranscription factor) NM_001423 EMP1 epithelial membrane Transmembrane,Glycoprotein 2054 6022 protein 1 NM_001431 EPB41L2 erythrocyteHypothetical protein, Structural 2055 6023 membrane protein protein,Cytoskeleton, Actin-binding band 4.1-like 2 NM_001432 EREG epiregulinAngiogenesis, Growth factor, 2056 6024 Mitogen, Glycoprotein, EGF-likedomain, Transmembrane, Signal NM_001440 EXTL3 exostoses (multiple)-Transferase, Glycosyltransferase, 2057 6025 like 3 Endoplasmicreticulum, Transmembrane, Signal-anchor, Glycoprotein NM_001444 FABP5fatty acid binding Transport, Lipid-binding, 3D- 2058 6026 protein 5(psoriasis- structure associated) NM_001449 FHL1 four and a half LIMCoiled coil, Transcription regulation, 2059 6027 domains 1 Nuclearprotein, Disease mutation, Anhidrotic ectodermal dysplasia, Repeat, LIMdomain, Metal-binding, Zinc, Developmental protein, Differentiation,Zinc-finger NM_001455 FOXO3A forkhead box O3A Transcription regulation,DNA- 2060 6028 binding, Nuclear protein, Apoptosis, Chromosomaltranslocation, Proto- oncogene, Phosphorylation NM_001456 FLNA filaminA, alpha Cytoskeleton, Actin-binding, Repeat, 2061 6029 (actin bindingprotein Phosphorylation, Polymorphism, 280) Disease mutation, Multigenefamily, Hypothetical protein NM_001462 FPRL1 formyl peptide G-proteincoupled receptor, 2062 6030 receptor-like 1 Transmembrane, Glycoprotein,Chemotaxis, Repeat, WD repeat NM_001465 FYB FYN binding protein SH3domain, Phosphorylation, 2063 6031 (FYB-120/130) Nuclear protein, Coiledcoil, Alternative splicing NM_001467 G6PT1 solute carrier familyTransmembrane, Transport, Sugar 2064 6032 37 (glycerol-6- transport,Endoplasmic reticulum, phosphate Alternative splicing, Glycogentransporter), storage disease, Disease mutation member 4 NM_001469 G22P1thyroid autoantigen Helicase, Nuclear protein, DNA- 2065 6033 70 kDa (Kuantigen) binding, Phosphorylation, Antigen, Systemic lupuserythematosus, Acetylation, 3D-structure NM_001478 GALGTUDP-N-acetyl-alpha- Hypothetical protein, Transferase, 2066 6034D-galactosamine:(N- Glycosyltransferase, acetylneuraminyl)-Transmembrane, Signal-anchor, galactosylglucosylceramide Golgi stack,Glycoprotein, N- Polymorphism acetylgalactosaminyl transferase(GalNAc-T) NM_001482 GATM glycine Transferase, Mitochondrion, Transit2067 6035 amidinotransferase peptide, 3D-structure, Alternative(L-arginine:glycine splicing amidinotransferase) NM_001483 GBASglioblastoma 2068 6036 amplified sequence NM_001487 GCN5L1 GCN5 general2069 6037 control of amino-acid synthesis 5-like 1 (yeast) NM_001493GDI1 GDP dissociation GTPase activation, Disease 2070 6038 inhibitor 1mutation NM_001500 GMDS GDP-mannose 4,6- Lyase, NADP 2071 6039dehydratase NM_001503 GPLD1 glycosylphosphatidyl Hydrolase,Glycoprotein, Signal, 2072 6040 inositol specific Hypothetical proteinphospholipase D1 NM_001504 CXCR3 chemokine (C—X—C G-protein coupledreceptor, 2073 6041 motif) receptor 3 Transmembrane, Glycoprotein,Antigen, Polymorphism NM_001517 GTF2H4 general transcriptionTranscription regulation, DNA repair, 2074 6042 factor IIH, Nuclearprotein polypeptide 4, 52 kDa NM_001518 GTF2I general transcriptionTranscription regulation, DNA- 2075 6043 factor II, i binding, Nuclearprotein, Phosphorylation, Repeat, Williams- Beuren syndrome, Alternativesplicing NM_001519 BRF1 BRF1 homolog, Transcription regulation,Activator, 2076 6044 subunit of RNA Nuclear protein, Repeat,Zinc-finger, polymerase III Metal-binding, Zinc, Alternativetranscription splicing, Hypothetical protein initiation factor IIIB (S.cerevisiae) NM_001520 GTF3C1 general transcription 2077 6045 factorIIIC, polypeptide 1, alpha 220 kDa NM_001528 HGFAC HGF activatorHydrolase, Glycoprotein, Plasma, 2078 6046 Serine protease, Kringle,Signal, EGF-like domain, Repeat, Zymogen NM_001531 MR1 major MHC,Glycoprotein, Transmembrane 2079 6047 histocompatibility complex, classI- related NM_001536 HRMT1L2 HMT1 hnRNP Transferase, Methyltransferase,2080 6048 methyltransferase- Nuclear protein, Alternative splicing like2 (S. cerevisiae) NM_001538 HSF4 F-box and leucine- Transcriptionregulation, Nuclear 2081 6049 rich repeat protein 8 protein,DNA-binding, Activator, Repressor, Heat shock, Multigene family,Alternative splicing NM_001539 DNAJA1 DnaJ (Hsp40) Chaperone, Repeat,Zinc, Metal- 2082 6050 homolog, subfamily binding, Prenylation,Lipoprotein, A, member 1 Multigene family NM_001550 IFRD1interferon-related 2083 6051 developmental regulator 1 NM_001551 IGBP1immunoglobulin B-cell activation, Phosphorylation 2084 6052 (CD79A)binding protein 1 NM_001554 CYR61 cysteine-rich, Plasmid, Chemotaxis,Cell adhesion, 2085 6053 angiogenic inducer, Growth factor binding,Heparin- 61 binding, Signal NM_001557 IL8RB interleukin 8 G-proteincoupled receptor, 2086 6054 receptor, beta Transmembrane, Glycoprotein,Chemotaxis, Polymorphism, Receptor NM_001558 IL10RA interleukin 10Receptor, Transmembrane, 2087 6055 receptor, alpha Glycoprotein, Signal,Polymorphism, 3D-structure NM_001567 INPPL1 inositol DNA repair 20886056 polyphosphate phosphatase-like 1 NM_001572 IRF7 interferonregulatory Transcription regulation, DNA- 2089 6057 factor 7 binding,Nuclear protein, Activator, Alternative splicing, Collagen NM_001607ACAA1 acetyl-Coenzyme A Acyltransferase, Transferase, Fatty 2090 6058acyltransferase 1 acid metabolism, Peroxisome, (peroxisomal 3- Transitpeptide, Polymorphism oxoacyl-Coenzyme A thiolase) NM_001618 ADPRT ADP-Transferase, Glycosyltransferase, 2091 6059 ribosyltransferase NAD,DNA-binding, Nuclear protein, (NAD+; poly (ADP- ADP-ribosylation,Zinc-finger, Zinc, ribose) polymerase) Polymorphism NM_001619 ADRBK1adrenergic, beta, Kinase, Receptor, Transferase, 2092 6060 receptorkinase 1 Serine/threonine-protein kinase, ATP-binding, Multigene family,3D- structure NM_001621 AHR aryl hydrocarbon Cell cycle, Transcriptionregulation, 2093 6061 receptor Activator, Receptor, DNA-binding, Nuclearprotein, Repeat, Polymorphism NM_001628 AKR1B1 aldo-keto reductaseOxidoreductase, NADP, Acetylation, 2094 6062 family 1, member B13D-structure, Polymorphism (aldose reductase) NM_001629 ALOX5AParachidonate 5- Transmembrane, Leukotriene 2095 6063 lipoxygenase-biosynthesis activating protein NM_001632 ALPP alkaline Hydrolase, Zinc,Magnesium, 2096 6064 phosphatase, Phosphorylation, Transmembrane,placental (Regan Placenta, Multigene family, isozyme) Glycoprotein,GPI-anchor, Signal, 3D-structure, Lipoprotein NM_001634 AMD1adenosylmethionine Spermidine biosynthesis, Lyase, 2097 6065decarboxylase 1 Decarboxylase, Pyruvate, Zymogen, 3D-structure NM_001637AOAH acyloxyacyl Hydrolase, Signal, Transmembrane, 2098 6066 hydrolaseGlycoprotein (neutrophil) NM_001643 APOA2 apolipoprotein A-II Transport,Lipid transport, HDL, 2099 6067 Signal, Pyrrolidone carboxylic acid,3D-structure NM_001654 ARAF1 v-raf murine Transferase, Serine/threonine-2100 6068 sarcoma 3611 viral protein kinase, Proto-oncogene, oncogenehomolog 1 Metal-binding, Zinc, ATP-binding, Phorbol-ester binding,Kinase NM_001657 AREG amphiregulin Glycoprotein, Cytokine, Growth 21016069 (schwannoma- factor, EGF-like domain, Signal, derived growthTransmembrane factor) NM_001662 ARF5 ADP-ribosylation GTP-binding,Multigene family, 2102 6070 factor 5 Myristate, Protein transport, Golgistack, Lipoprotein NM_001665 ARHG ras homolog gene GTP-binding,Prenylation, 2103 6071 family, member G Lipoprotein (rho G) NM_001667ARL2 sorting nexin 15 GTP-binding, Multigene family, 2104 6072Hypothetical protein, Transport, Protein transport, Alternative splicingNM_001670 ARVCF armadillo repeat Hypothetical protein, Cell adhesion,2105 6073 gene deletes in Cytoskeleton, Structural protein,velocardiofacial Repeat, Coiled coil, Alternative syndrome splicingNM_001671 ASGR1 asialoglycoprotein Lectin, Glycoprotein, Receptor, 21066074 receptor 1 Endocytosis, Transmembrane, Calcium, Signal-anchor,Phosphorylation, 3D-structure NM_001677 ATP1B1 ATPase, Na+/K+Transferase, Kinase, ATP-binding, 2107 6075 transporting, beta 1Sodium/potassium transport, polypeptide Transmembrane, Glycoprotein,Multigene family, Signal-anchor, Alternative splicing NM_001678 ATP1B2ATPase, Na+/K+ Sodium/potassium transport, 2108 6076 transporting, beta2 Transmembrane, Glycoprotein, polypeptide Multigene family,Signal-anchor NM_001679 ATP1B3 ATPase, Na+/K+ Sodium/potassiumtransport, 2109 6077 transporting, beta 3 Transmembrane, Glycoprotein,polypeptide Multigene family, Signal-anchor NM_001681 ATP2A2 ATPase,Ca++ Hydrolase, Calcium transport, 2110 6078 transporting, cardiacTransmembrane, Phosphorylation, muscle, slow twitch 2 ATP-binding,Metal-binding, Magnesium, Calcium-binding, Multigene family, Alternativesplicing, Disease mutation, Epilepsy NM_001693 ATP6V1B2 ATPase, H+Hydrolase, ATP synthesis, Hydrogen 2111 6079 transporting, iontransport, Multigene family lysosomal 56/58 kDa, V1 subunit B, isoform 2NM_001706 BCL6 B-cell Nuclear protein, Transcription 2112 6080CLL/lymphoma 6 regulation, Activator, DNA-binding, (zinc finger proteinZinc-finger, Metal-binding, Repeat, 51) Proto-oncogene, Chromosomaltranslocation, Polymorphism NM_001712 CEACAM1 carcinoembryonicAlternative splicing, Immunoglobulin 2113 6081 antigen-related celldomain, Signal, Transmembrane, adhesion molecule 1 Glycoprotein, Repeat,Pyrrolidone (biliary glycoprotein) carboxylic acid, Hypothetical proteinNM_001714 BICD1 Bicaudal D homolog Golgi stack, Coiled coil, Alternative2114 6082 1 (Drosophila) splicing NM_001716 BLR1 Burkitt lymphoma B-cellactivation, G-protein coupled 2115 6083 receptor 1, GTP receptor,Transmembrane, binding protein Glycoprotein, Alternative splicing,(chemokine (C—X—C Polymorphism motif) receptor 5) NM_001721 BMX BMXnon-receptor Transferase, Tyrosine-protein 2116 6084 tyrosine kinasekinase, Phosphorylation, ATP- binding, SH3 domain, SH2 domain NM_001725BPI bactericidal/permeability- Antibiotic, Signal, Transmembrane, 21176085 increasing Glycoprotein, 3D-structure protein NM_001728 BSG basigin(OK blood Immunoglobulin domain, 2118 6086 group) Transmembrane,Glycoprotein, Signal, Antigen, Blood group antigen, PolymorphismNM_001730 KLF5 Kruppel-like factor 5 Transcription regulation, DNA- 21196087 (intestinal) binding, Nuclear protein, Repeat, Zinc-finger,Metal-binding, Activator NM_001731 BTG1 B-cell translocationProto-oncogene, Chromosomal 2120 6088 gene 1, anti- translocationproliferative NM_001736 C5R1 complement G-protein coupled receptor, 21216089 component 5 Transmembrane, Glycoprotein, receptor 1 (C5a Sulfation,Chemotaxis ligand) NM_001745 CAMLG calcium modulating Transmembrane 21226090 ligand NM_001747 CAPG capping protein Nuclear protein,Actin-binding, 2123 6091 (actin filament), Repeat, 3D-structure, Actincapping gelsolin-like NM_001749 CAPNS1 calpain, small Calcium-binding,Repeat, 3D- 2124 6092 subunit 1 structure NM_001750 CAST calpastatinRepeat, Thiol protease inhibitor, 2125 6093 Alternative splicing,Phosphorylation, Signal transduction inhibitor NM_001767 CD2 CD2 antigen(p50), Immunoglobulin domain, T-cell, 2126 6094 sheep red blood cellGlycoprotein, Antigen, receptor Transmembrane, Cell adhesion, Repeat,Signal, Polymorphism, 3D- structure NM_001769 CD9 CD9 antigen (p24)Glycoprotein, Antigen, 2127 6095 Transmembrane, Lipoprotein,Phosphorylation NM_001771 CD22 CD22 antigen Cell adhesion, Lectin,Antigen, 2128 6096 Transmembrane, Signal, Glycoprotein, Immunoglobulindomain, Repeat, Phosphorylation, Alternative splicing, PolymorphismNM_001773 CD34 CD34 antigen Cell adhesion, Antigen, Signal, 2129 6097Transmembrane, Glycoprotein, Phosphorylation, Alternative splicingNM_001774 CD37 CD37 antigen Glycoprotein, Antigen, 2130 6098Transmembrane, Hypothetical protein NM_001776 ENTPD1 ectonucleosideHydrolase, Transmembrane, 2131 6099 triphosphate Antigen, Glycoprotein,Calcium, diphosphohydrolase 1 Magnesium, Alternative splicing,Lipoprotein, Palmitate NM_001777 CD47 CD47 antigen (Rh- Cell adhesion,Antigen, Signal, 2132 6100 related antigen, Transmembrane, Glycoprotein,integrin-associated Alternative splicing signal transducer) NM_001780CD63 CD63 antigen Glycoprotein, Antigen, 2133 6101 (melanoma 1Transmembrane, Lysosome antigen) NM_001781 CD69 CD69 antigen (p60,Antigen, Signal-anchor, 2134 6102 early T-cell Transmembrane, Lectin,activation antigen) Glycoprotein, Phosphorylation, 3D- structureNM_001800 CDKN2D cyclin-dependent Cell cycle, Anti-oncogene, Repeat,2135 6103 kinase inhibitor 2D ANK repeat, 3D-structure (p19, inhibitsCDK4) NM_001803 CDW52 CDW52 antigen Antigen, Signal, Glycoprotein, GPI-2136 6104 (CAMPATH-1 anchor, Membrane, Polymorphism, antigen)Lipoprotein NM_001805 CEBPE CCAAT/enhancer Transcription regulation,Activator, 2137 6105 binding protein DNA-binding, Nuclear protein,(C/EBP), epsilon Phosphorylation NM_001806 CEBPG CCAAT/enhancerTranscription regulation, Activator, 2138 6106 binding proteinDNA-binding, Nuclear protein (C/EBP), gamma NM_001808 CELL carboxylester lipase 2139 6107 pseudogene NM_001815 CEACAM3 carcinoembryonicImmunoglobulin domain, Antigen, 2140 6108 antigen-related cell Signal,Glycoprotein, adhesion molecule 3 Transmembrane, Alternative splicing,Polymorphism NM_001816 CEACAM8 carcinoembryonic Immunoglobulin domain,Antigen, 2141 6109 antigen-related cell Signal, Glycoprotein,GPI-anchor, adhesion molecule 8 Repeat, Polymorphism, LipoproteinNM_001817 CEACAM4 carcinoembryonic Antigen 2142 6110 antigen-relatedcell adhesion molecule 4 NM_001828 CLC Charot-Leyden Hydrolase, Serineesterase, Lipid 2143 6111 crystal protein degradation, Galectin,Acetylation, 3D-structure, Polymorphism NM_001835 CLTCL1 clathrin, heavyCoated pits, Alternative splicing 2144 6112 polypeptide-like 1 NM_001838CCR7 chemokine (C-C G-protein coupled receptor, 2145 6113 motif)receptor 7 Transmembrane, Glycoprotein, Signal NM_001839 CNN3 calponin3, acidic Calmodulin-binding, Actin-binding, 2146 6114 Multigene family,Repeat NM_001853 COL9A3 collagen, type IX, Hypothetical protein,Collagen, 2147 6115 alpha 3 Extracellular matrix, Connective tissue,Repeat, Hydroxylation, Glycoprotein, Signal, Polymorphism NM_001882CRHBP corticotropin Glycoprotein, Signal 2148 6116 releasing hormonebinding protein NM_001889 CRYZ crystallin, zeta Oxidoreductase, NADP,Zinc 2149 6117 (quinone reductase) NM_001894 CSNK1E casein kinase 1,Transferase, Serine/threonine- 2150 6118 epsilon protein kinase,ATP-binding, Phosphorylation, Multigene family NM_001907 CTRLchymotrypsin-like Hydrolase, Protease, Serine 2151 6119 protease,Transferase, Serine/threonine-protein kinase, ATP-binding,Phosphorylation, Golgi stack, Nuclear protein, Glycoprotein, Zymogen,Signal NM_001909 CTSD cathepsin D Hydrolase, Aspartyl protease, 21526120 (lysosomal aspartyl Glycoprotein, Lysosome, Signal, protease)Zymogen, Polymorphism, Alzheimer's disease, 3D-structure NM_001911 CTSGcathepsin G Hydrolase, Serine protease, 2153 6121 Zymogen, Glycoprotein,Signal, Polymorphism, 3D-structure NM_001921 DCTD dCMP deaminaseHydrolase, Allosteric enzyme, 2154 6122 Nucleotide biosynthesis, ZincNM_001925 DEFA4 defensin, alpha 4, Defensin, Antibiotic, Fungicide, 21556123 corticostatin Signal NM_001939 DRP2 dystrophin related Structuralprotein, Cytoskeleton, 2156 6124 protein 2 Repeat, Zinc-finger NM_001940DRPLA dentatorubral- Triplet repeat expansion, 2157 6125 pallidoluysianPolymorphism, Epilepsy atrophy (atrophin-1) NM_001946 DUSP6 dualspecificity Hydrolase, Polymorphism, 2158 6126 phosphatase 6 Alternativesplicing, 3D-structure NM_001951 E2F5 E2F transcription Transcriptionregulation, Activator, 2159 6127 factor 5, p130- DNA-binding, Nuclearprotein, binding Polymorphism NM_001953 ECGF1 endothelial cellTransferase, Glycosyltransferase, 2160 6128 growth factor 1 Growthfactor, Chemotaxis, (platelet-derived) Angiogenesis, Repeat,Polymorphism, Disease mutation NM_001964 EGR1 early growth Transcriptionregulation, Activator, 2161 6129 response 1 DNA-binding, Nuclearprotein, Repeat, Zinc-finger, Metal-binding NM_001965 EGR4 early growthNuclear protein, Transcription 2162 6130 response 4 regulation,DNA-binding, Zinc-finger, Metal-binding, Repeat NM_001970 EIF5Aeukaryotic Protein biosynthesis, Initiation factor, 2163 6131translation initiation Hypusine, 3D-structure factor 5A NM_001972 ELA2elastase 2, Hydrolase, Serine protease, 2164 6132 neutrophilGlycoprotein, Signal, 3D-structure, Disease mutation NM_001992 F2Rcoagulation factor II G-protein coupled receptor, 2165 6133 (thrombin)receptor Transmembrane, Glycoprotein, Signal, Blood coagulation,Phosphorylation, Polymorphism, 3D- structure, Receptor NM_001995 FACL1fatty-acid-Coenzyme Ligase, Fatty acid metabolism, 2166 6134 A ligase,long-chain 2 Magnesium, Multigene family, Hypothetical protein NM_001996FBLN1 fibulin 1 Signal, Alternative splicing, 2167 6135 Glycoprotein,Extracellular matrix, Repeat, EGF-like domain, Calcium- binding,Chromosomal translocation, Polymorphism, Hypothetical protein NM_001999FBN2 fibrillin 2 (congenital Hypothetical protein, EGF-like 2168 6136contractural domain, Extracellular matrix, arachnodactyly)Calcium-binding, Glycoprotein, Repeat, Signal, Multigene family, Diseasemutation, Polymorphism NM_002000 FCAR Fc fragment of IgA, Receptor,Glycoprotein, 2169 6137 receptor for Transmembrane, IgA-binding protein,Immunoglobulin domain, Repeat, Signal, Alternative splicing NM_002003FCN1 ficolin Lectin, Collagen, Repeat, 2170 6138 (collagen/fibrinogenGlycoprotein, Signal, Multigene domain containing) 1 family NM_002005FES feline sarcoma Transferase, Tyrosine-protein 2171 6139 oncogenekinase, Proto-oncogene, ATP- binding, Phosphorylation, SH2 domainNM_002010 FGF9 fibroblast growth Growth factor, Differentiation, 21726140 factor 9 (glia- Mitogen, Heparin-binding, activating factor)Glycoprotein, 3D-structure NM_002013 FKBP3 FK506 binding Isomerase,Rotamase, Nuclear 2173 6141 protein 3, 25 kDa protein, 3D-structureNM_002014 FKBP4 FK506 binding Isomerase, Rotamase, Repeat, TPR 2174 6142protein 4, 59 kDa repeat, Nuclear protein, Phosphorylation, 3D-structureNM_002017 FLI1 Friend leukemia Transcription regulation, Activator, 21756143 virus integration 1 DNA-binding, Nuclear protein, Alternativesplicing, Proto-oncogene, Chromosomal translocation, 3D- structureNM_002018 FLII flightless I homolog Developmental protein, Repeat, 21766144 (Drosophila) Leucine-rich repeat NM_002029 FPR1 formyl peptideG-protein coupled receptor, 2177 6145 receptor 1 Transmembrane,Glycoprotein, Chemotaxis, Polymorphism NM_002032 FTH1 ferritin, heavyTransport, Ion transport, Ionic 2178 6146 polypeptide 1 channel,Chloride channel, Chloride, Calcium, Alternative splicing, Diseasemutation, Polymorphism, Vision, Transmembrane, Phosphorylation, Ironstorage, Metal- binding, 3D-structure NM_002033 FUT4 fucosyltransferase4 Transferase, Glycosyltransferase, 2179 6147 (alpha (1,3)Transmembrane, Glycoprotein, fucosyltransferase, Signal-anchor, Golgistack myeloid-specific) NM_002035 FVT1 follicular lymphomaProto-oncogene, Chromosomal 2180 6148 variant translocation 1translocation, Oxidoreductase, Signal NM_002037 FYN FYN oncogeneHypothetical protein, ATP-binding, 2181 6149 related to SRC, SH3 domain,Transferase, Kinase, FGR, YES Tyrosine-protein kinase, Proto- oncogene,Phosphorylation, Myristate, SH2 domain, Palmitate, Lipoprotein,3D-structure, Polymorphism NM_002046 GAPD glyceraldehyde-3- Glycolysis,NAD, Oxidoreductase, 2182 6150 phosphate Multigene family dehydrogenaseNM_002051 GATA3 GATA binding Hypothetical protein, Transcription 21836151 protein 3 regulation, Activator, DNA-binding, Zinc-finger, Nuclearprotein, T-cell, Alternative splicing NM_002061 GCLM glutamate-cysteineLigase, Glutathione biosynthesis 2184 6152 ligase, modifier subunitNM_002064 GLRX glutaredoxin Redox-active center, Electron 2185 6153(thioltransferase) transport, Acetylation, Polymorphism, 3D-structureNM_002068 GNA15 guanine nucleotide GTP-binding, Transducer, Multigene2186 6154 binding protein (G family, ADP-ribosylation protein), alpha 15(Gq class) NM_002069 GNAI1 guanine nucleotide Hypothetical protein,GTP-binding, 2187 6155 binding protein (G Transducer, ADP-ribosylation,protein), alpha Multigene family, Myristate, inhibiting activityPalmitate, Lipoprotein, 3D-structure polypeptide 1 NM_002070 GNAI2guanine nucleotide GTP-binding, Transducer, ADP- 2188 6156 bindingprotein (G ribosylation, Multigene family, protein), alpha Myristate,Palmitate, Lipoprotein inhibiting activity polypeptide 2 NM_002073 GNAZguanine nucleotide GTP-binding, Transducer, ADP- 2189 6157 bindingprotein (G ribosylation, Multigene family, protein), alpha zLipoprotein, Palmitate, Myristate, polypeptide Membrane NM_002081 GPC1glypican 1 Proteoglycan, Heparan sulfate, 2190 6158 Glycoprotein,Signal, GPI-anchor, Lipoprotein NM_002082 GPRK6 G protein-coupledTransferase, Serine/threonine- 2191 6159 receptor kinase 6 proteinkinase, ATP-binding, Phosphorylation, Lipoprotein, Palmitate,Alternative splicing, Kinase, Receptor, Hypothetical protein NM_002086GRB2 growth factor SH2 domain, SH3 domain, Repeat, 2192 6160receptor-bound Alternative splicing, 3D-structure protein 2 NM_002087GRN granulin Cytokine, Repeat, Glycoprotein, 2193 6161 Signal,Alternative splicing, Polymorphism, 3D-structure, Hypothetical proteinNM_002092 GRSF1 G-rich RNA Hypothetical protein, RNA-binding, 2194 6162sequence binding Repeat factor 1 NM_002093 GSK3B glycogen synthaseTransferase, Serine/threonine- 2195 6163 kinase 3 beta protein kinase,ATP-binding, Wnt signaling pathway, Phosphorylation, Multigene family,Alternative splicing, 3D-structure NM_002096 GTF2F1 generaltranscription Transcription regulation, DNA- 2196 6164 factor IIF,binding, Nuclear protein, polypeptide 1, Phosphorylation, 3D-structure74 kDa NM_002097 GTF3A general transcription Transcription regulation,Zinc-finger, 2197 6165 factor IIIA Metal-binding, DNA-binding, RNA-binding, Repeat, Nuclear protein, Polymorphism, Initiation factorNM_002103 GYS1 glycogen synthase 1 Glycogen biosynthesis, Transferase,2198 6166 (muscle) Glycosyltransferase, Allosteric enzyme,Phosphorylation, Disease mutation, Diabetes mellitus, Polymorphism,Hypothetical protein NM_002104 GZMK granzyme K (serine Hydrolase, Serineprotease, 2199 6167 protease, granzyme Zymogen, Signal, 3D-structure 3;tryptase II) NM_002105 H2AFX H2A histone family, Chromosomal protein,Nucleosome 2200 6168 member X core, Nuclear protein, DNA-binding,Multigene family, Acetylation NM_002107 H3F3A H3 histone, family Nuclearprotein, Chromosomal 2201 6169 3A protein, DNA-binding, Nucleosome core,Multigene family NM_002108 HAL histidine ammonia- Lyase, Histidinemetabolism, 2202 6170 lyase Polymorphism NM_002109 HARS histidyl-tRNAAminoacyl-tRNA synthetase, Protein 2203 6171 synthetase biosynthesis,Ligase, ATP-binding, Hypothetical protein, Repeat, WD repeat NM_002110HCK hemopoietic cell Transferase, Tyrosine-protein 2204 6172 kinasekinase, Phosphorylation, ATP- binding, Lipoprotein, Myristate,Palmitate, SH2 domain, SH3 domain, Alternative initiation, 3D- structureNM_002115 HK3 hexokinase 3 (white Kinase, Transferase, Glycolysis, 22056173 cell) Allosteric enzyme, Repeat, ATP- binding, Membrane NM_002131HMGA1 high mobility group Nuclear protein, Chromosomal 2206 6174 AT-hook1 protein, DNA-binding, Repeat, Transcription regulation, Alternativesplicing, Phosphorylation, Acetylation, Chromosomal translocation,3D-structure NM_002133 HMOX1 heme oxygenase Cyclin, Heme,Oxidoreductase, 2207 6175 (decycling) 1 Microsome, Multigene family, 3D-structure NM_002134 HMOX2 heme oxygenase Heme, Oxidoreductase,Microsome, 2208 6176 (decycling) 2 Multigene family, Repeat NM_002136HNRPA1 heterogeneous Hypothetical protein, Nucleocapsid, 2209 6177nuclear Ribonucleoprotein, Nuclear protein, ribonucleoprotein A1RNA-binding, Repeat, Methylation, Alternative splicing, 3D-structure,Polymorphism NM_002139 RBMX RNA binding motif Hypothetical protein,Nuclear 2210 6178 protein, X-linked protein, RNA-binding,Ribonucleoprotein, Glycoprotein NM_002155 HSPA6 heat shock 70 kDaATP-binding, Heat shock, Multigene 2211 6179 protein 6 (HSP70B′) familyNM_002156 HSPD1 heat shock 60 kDa Chaperone, ATP-binding, 2212 6180protein 1 Mitochondrion, Transit peptide (chaperonin) NM_002157 HSPE1heat shock 10 kDa Chaperone, Mitochondrion, Heat 2213 6181 protein 1shock, Acetylation (chaperonin 10) NM_002162 ICAM3 intercellularImmunoglobulin domain, Cell 2214 6182 adhesion molecule 3 adhesion,Glycoprotein, Transmembrane, Repeat, Signal, Phosphorylation NM_002180IGHMBP2 immunoglobulin mu Hydrolase, Helicase, ATP-binding, 2215 6183binding protein 2 DNA-binding, Nuclear protein, Transcriptionregulation, Activator, 3D-structure NM_002191 INHA inhibin, alpha Growthfactor, Hormone, 2216 6184 Glycoprotein, Signal, Polymorphism NM_002194INPP1 inositol Hydrolase, Lithium 2217 6185 polyphosphate-1- phosphataseNM_002205 ITGA5 integrin, alpha 5 Integrin, Cell adhesion, Receptor,2218 6186 (fibronectin receptor, Glycoprotein, Transmembrane, alphapolypeptide) Signal, Calcium, Repeat NM_002209 ITGAL integrin, alpha LIntegrin, Cell adhesion, Receptor, 2219 6187 (antigen CD11AGlycoprotein, Transmembrane, (p180), lymphocyte Signal, 3D-structure,Magnesium, function-associated Calcium, Repeat, Alternative antigen 1;alpha splicing, Hypothetical protein polypeptide) NM_002218 ITIH4inter-alpha (globulin) Acute phase, Serine protease 2220 6188 inhibitorH4 (plasma inhibitor, Repeat, Signal, Multigene Kallikrein-sensitivefamily, Glycoprotein, Alternative glycoprotein) splicing, PolymorphismNM_002220 ITPKA inositol 1,4,5- Kinase, Transferase, Calmodulin- 22216189 trisphosphate 3- binding kinase A NM_002222 ITPR1 inositol 1,4,5-Receptor, Transmembrane, 2222 6190 triphosphate Phosphorylation,Endoplasmic receptor, type 1 reticulum, Ionic channel, Ion transport,Calcium channel, Alternative splicing, Repeat NM_002226 JAG2 jagged 2Calcium-binding, EGF-like domain, 2223 6191 Glycoprotein, Developmentalprotein, Repeat, Signal, Transmembrane, Alternative splicing NM_002228JUN v-jun sarcoma virus Proto-oncogene, Transcription 2224 6192 17oncogene regulation, DNA-binding, 3D- homolog (avian) structure, Nuclearprotein, Phosphorylation, Polymorphism NM_002236 KCNF1 potassiumvoltage- Transport, Ion transport, Ionic 2225 6193 gated channel,channel, Voltage-gated channel, subfamily F, member 1 Potassium channel,Potassium, Potassium transport, Transmembrane, Multigene familyNM_002243 KCNJ15 potassium inwardly- Hypothetical protein, Ionicchannel, 2226 6194 rectifying channel, Ion transport, Voltage-gatedsubfamily J, member channel, Transmembrane, 15 Potassium transportNM_002250 KCNN4 potassium Ionic channel, Transmembrane, Ion 2227 6195intermediate/small transport, Calmodulin-binding conductancecalcium-activated channel, subfamily N, member 4 NM_002258 KLRB1 killercell lectin-like 2228 6196 receptor subfamily B, member 1 NM_002267KPNA3 karyopherin alpha 3 Hypothetical protein, Transport, 2229 6197(importin alpha 4) Protein transport, Repeat, Nuclear protein,Polymorphism NM_002271 KPNB3 karyopherin Hypothetical protein,Transport, 2230 6198 (importin) beta 3 Protein transport, Repeat,Nuclear protein, Polymorphism NM_002273 KRT8 keratin 8 Intermediatefilament, Coiled coil, 2231 6199 Keratin, Phosphorylation NM_002275KRT15 keratin 15 Intermediate filament, Coiled coil, 2232 6200 KeratinNM_002277 KRTHA1 keratin, hair, acidic, 1 Intermediate filament, Coiledcoil, 2233 6201 Keratin NM_002278 KRTHA2 keratin, hair, acidic, 2Intermediate filament, Coiled coil, 2234 6202 Keratin NM_002282 KRTHB3keratin, hair, basic, 3 Coiled coil, Intermediate filament 2235 6203NM_002296 LBR lamin B receptor Receptor, Transmembrane, 2236 6204Phosphorylation, Nuclear protein, DNA-binding NM_002298 LCP1 lymphocytecytosolic Calcium-binding, Phosphorylation, 2237 6205 protein 1(L-plastin) Actin-binding, Repeat, Polymorphism NM_002299 LCT lactaseHydrolase, Glycosidase, Zymogen, 2238 6206 Signal, Transmembrane, RepeatNM_002300 LDHB lactate Oxidoreductase, NAD, Glycolysis, 2239 6207dehydrogenase B Multigene family, Disease mutation, 3D-structureNM_002306 LGALS3 lectin, galactoside- Galectin, Lectin, IgE-bindingprotein, 2240 6208 binding, soluble, 3 Repeat, Phosphorylation,(galectin 3) Acetylation, Nuclear protein, Polymorphism, 3D-structureNM_002311 LIG3 ligase III, DNA, ATP- DNA repair, DNA replication, DNA2241 6209 dependent recombination, Cell division, Ligase, ATP-binding,Zinc-finger, Nuclear protein, Alternative splicing, 3D- structure,Hypothetical protein NM_002313 ABLIM1 actin binding LIM LIM domain,Metal-binding, Zinc, 2242 6210 protein 1 Hypothetical protein NM_002316LMX1B LIM homeobox DNA-binding, Homeobox, LIM 2243 6211 transcriptionfactor 1, domain, Metal-binding, Nuclear beta protein, Zinc,Developmental protein, Repeat, Activator, Transcription regulation,Alternative splicing, Disease mutation NM_002332 LRP1 low densityReceptor, Transmembrane, Repeat, 2244 6212 lipoprotein-relatedEndocytosis, Glycoprotein, Signal, protein 1 (alpha-2- Calcium-binding,EGF-like domain, macroglobulin Coated pits, 3D-structure, receptor)Polymorphism NM_002335 LRP5 low density Receptor, Lipoprotein 2245 6213lipoprotein receptor- related protein 5 NM_002337 LRPAP1 low densitySignal, Heparin-binding, 2246 6214 lipoprotein receptor- Glycoprotein,Antigen, 3D-structure, related protein Polymorphism associated protein 1NM_002339 LSP1 lymphocyte-specific T-cell, Phosphorylation, 2247 6215protein 1 Polymorphism NM_002341 LTB lymphotoxin beta Cytokine,Transmembrane, 2248 6216 (TNF superfamily, Glycoprotein, Signal-anchor,member 3) Alternative splicing, Polymorphism NM_002343 LTFlactotransferrin Glycoprotein, Iron transport, Metal- 2249 6217 binding,Transport, Repeat, Signal, Polymorphism, 3D-structure NM_002357 MAD MAXdimerization Nuclear protein, DNA-binding, 2250 6218 protein 1Transcription regulation, Repressor, 3D-structure NM_002375 MAP4microtubule- Hypothetical protein, Microtubule, 2251 6219 associatedprotein 4 Repeat, Phosphorylation, Alternative splicing NM_002382 MAXMAX protein Hypothetical protein, Transcription 2252 6220 regulation,Activator, Repressor, Nuclear protein, DNA-binding, Phosphorylation,Alternative splicing, 3D-structure NM_002394 SLC3A2 solute carrierfamily Glycoprotein, Transmembrane, 2253 6221 3 (activators ofSignal-anchor dibasic and neutral amino acid transport), member 2NM_002402 MEST mesoderm specific Aromatic hydrocarbons catabolism, 22546222 transcript homolog Detoxification, Hydrolase, (mouse) Hypotheticalprotein NM_002406 MGAT1 mannosyl (alpha- Transferase,Glycosyltransferase, 2255 6223 1,3-)-glycoprotein Transmembrane,Signal-anchor, beta-1,2-N- Golgi stack, Hypothetical proteinacetylglucosaminyltransferase NM_002419 MAP3K11 mitogen-activatedATP-binding, Kinase, SH3 domain, 2256 6224 protein kinaseSerine/threonine-protein kinase, kinase kinase 11 Transferase NM_002424MMP8 matrix Hydrolase, Metalloprotease, 2257 6225 metalloproteinase 8Glycoprotein, Calcium-binding, (neutrophil Metal-binding, Zinc, Zymogen,collagenase) Collagen degradation, Extracellular matrix, Signal,3D-structure NM_002431 MNAT1 menage a trois 1 Transcription regulation,Cell cycle, 2258 6226 (CAK assembly Nuclear protein, Zinc-finger, 3D-factor) structure NM_002432 MNDA myeloid cell nuclear Interferoninduction, Nuclear protein, 2259 6227 differentiation DNA-binding,Transcription antigen regulation, Activator, Repressor, PolymorphismNM_002435 MPI mannose phosphate Isomerase, Zinc, Disease mutation 22606228 isomerase NM_002442 MSI1 musashi homolog 1 RNA-binding 2261 6229(Drosophila) NM_002453 MTIF2 mitochondrial Initiation factor, Proteinbiosynthesis, 2262 6230 translational initiation GTP-binding, Transitpeptide, factor 2 Mitochondrion, Polymorphism NM_002455 MTX1 metaxin 1Mitochondrion, Outer membrane, 2263 6231 Transmembrane, Transport,Protein transport NM_002475 MLC1SA myosin light chain 1 Myosin, Muscleprotein, Multigene 2264 6232 slow a family NM_002483 CEACAM6carcinoembryonic Immunoglobulin domain, Signal, 2265 6233antigen-related cell Antigen, Glycoprotein, GPI-anchor, adhesionmolecule 6 Repeat, Lipoprotein (non-specific cross reacting antigen)NM_002486 NCBP1 nuclear cap binding Transport, mRNA transport, Nuclear2266 6234 protein subunit 1, protein, RNA-binding, 3D-structure 80 kDaNM_002492 NDUFB5 NADH Oxidoreductase, NAD, Ubiquinone, 2267 6235dehydrogenase Mitochondrion, Transit peptide (ubiquinone) 1 betasubcomplex, 5, 16 kDa NM_002495 NDUFS4 NADH Oxidoreductase, NAD,Ubiquinone, 2268 6236 dehydrogenase Mitochondrion, Transit peptide,(ubiquinone) Fe—S Polymorphism protein 4, 18 kDa (NADH-coenzyme Qreductase) NM_002499 NEO1 neogenin homolog 1 Cell adhesion, Repeat,Signal, 2269 6237 (chicken) Transmembrane, Immunoglobulin domain,Glycoprotein, Alternative splicing NM_002512 NME2 non-metastatic cellsTransferase, Kinase, ATP-binding, 2270 6238 2, protein (NM23B) Nuclearprotein, Anti-oncogene, expressed in DNA-binding, Transcriptionregulation, Activator, 3D-structure NM_002517 NPAS1 neuronal PAS Repeat,DNA-binding, Nuclear 2271 6239 domain protein 1 protein, Transcriptionregulation NM_002520 NPM1 nucleophosmin Hypothetical protein,Transcription 2272 6240 (nucleolar regulation, Nuclear protein, DNA-phosphoprotein B23, binding, Zinc-finger, Proto- numatrin) oncogene,Chromosomal translocation, Alternative splicing, Repeat, Coiled coil,3D-structure, Metal-binding, Receptor, Multigene family,Phosphorylation, RNA- NM_002524 NRAS neuroblastoma RAS Hypotheticalprotein, RNA-binding, 2273 6241 viral (v-ras) Repeat, Alternativesplicing, Proto- oncogene homolog oncogene, GTP-binding, Prenylation,Lipoprotein, Disease mutation NM_002528 NTHL1 nth endonuclease III-Hydrolase, Nuclease, Endonuclease, 2274 6242 like 1 (E. coli)Multifunctional enzyme, DNA repair, Glycosidase, Lyase, Iron-sulfur,4Fe—4S, Nuclear protein, Polymorphism NM_002532 NUP88 nucleoporin 88 kDaNuclear protein, Transport, Coiled 2275 6243 coil NM_002541 OGDHoxoglutarate (alpha- Glycolysis, Oxidoreductase, 2276 6244ketoglutarate) Flavoprotein, Thiamine dehydrogenase pyrophosphate,Mitochondrion, (lipoamide) Transit peptide, Hypothetical proteinNM_002543 OLR1 oxidised low density Lectin, Lipoprotein, Receptor 22776245 lipoprotein (lectin- like) receptor 1 NM_002553 ORC5L originrecognition DNA replication, Nuclear protein, 2278 6246 complex, subunit5- ATP-binding, Polymorphism like (yeast) NM_002555 SLC22A1L solutecarrier family Hypothetical protein 2279 6247 22 (organic cationtransporter), member 1-like NM_002557 OVGP1 oviductal Glycoprotein,Fertilization, Signal, 2280 6248 glycoprotein 1, Polymorphism 120 kDa(mucin 9, oviductin) NM_002564 P2RY2 purinergic receptor G-proteincoupled receptor, 2281 6249 P2Y, G-protein Transmembrane, Glycoproteincoupled, 2 NM_002573 PAFAH1B3 platelet-activating Hydrolase, Lipiddegradation 2282 6250 factor acetylhydrolase, isoform Ib, gamma subunit29 kDa NM_002574 PRDX1 peroxiredoxin 1 Antioxidant, Peroxidase, 22836251 Oxidoreductase, Redox-active center NM_002576 PAK1 p21/Cdc42/Rac1-Apoptosis, Transferase, 2284 6252 activated kinase 1Serine/threonine-protein kinase, (STE20 homolog, ATP-binding,Phosphorylation, 3D- yeast) structure, Kinase NM_002585 PBX1 pre-B-cellleukemia Transcription regulation, DNA- 2285 6253 transcription factor 1binding, Nuclear protein, Activator, Repressor, Homeobox, Proto-oncogene, Chromosomal translocation, Alternative splicing,Steroidogenesis, Sexual differentiation, 3D-structure, PhosphorylationNM_002587 PCDH1 protocadherin 1 Cell adhesion, Transmembrane, 2286 6254(cadherin-like 1) Calcium-binding, Repeat, Signal, Alternative splicingNM_002598 PDCD2 programmed cell Zinc-finger, DNA-binding, Nuclear 22876255 death 2 protein, Apoptosis NM_002601 PDE6D phosphodiesteraseHydrolase, cGMP, Vision, 3D- 2288 6256 6D, cGMP-specific, structure rod,delta NM_002608 PDGFB platelet-derived Mitogen, Growth factor, Proto-2289 6257 growth factor beta oncogene, Platelet, Signal, polypeptide(simian Pharmaceutical, 3D-structure, sarcoma viral (v-sis)Polymorphism, Chromosomal oncogene homolog) translocation NM_002611 PDK2pyruvate Kinase, Transferase, Transit peptide, 2290 6258 dehydrogenaseMitochondrion, Multigene family kinase, isoenzyme 2 NM_002613 PDPK13-phosphoinositide Transferase, Serine/threonine- 2291 6259 dependentprotein protein kinase, ATP-binding, kinase-1 Phosphorylation, Membrane,Alternative splicing, Kinase NM_002616 PER1 period homolog 1Transcription regulation, Nuclear 2292 6260 (Drosophila) protein,Repeat, Biological rhythms, Alternative splicing NM_002621 PFC properdinP factor, Signal, Complement alternate 2293 6261 complement pathway,Glycoprotein, Repeat, Disease mutation NM_002629 PGAM1 phosphoglycerateIsomerase, Hydrolase, Glycolysis, 2294 6262 mutase 1 (brain)Acetylation, 3D-structure NM_002631 PGD phosphogluconate Oxidoreductase,Pentose shunt, 2295 6263 dehydrogenase NADP NM_002633 PGM1phosphoglucomutase 1 Isomerase, Phosphorylation, 2296 6264 Magnesium,Polymorphism, Alternative splicing, Hypothetical protein NM_002635SLC25A3 solute carrier family Mitochondrion, Inner membrane, 2297 626525 (mitochondrial Repeat, Transit peptide, carrier; phosphateTransmembrane, Transport, carrier), member 3 Symport, Alternativesplicing, Hypothetical protein NM_002640 SERPINB8 serine (or cysteine)Protease inhibitor, Serine protease 2298 6266 proteinase inhibitor,inhibitor, Serpin clade B (ovalbumin), member 8 NM_002649 PIK3CGphosphoinositide-3- Kinase, Transferase, Multigene 2299 6267 kinase,catalytic, family, 3D-structure gamma polypeptide NM_002650 PIK4CAphosphatidylinositol Transferase, Kinase, Alternative 2300 62684-kinase, catalytic, splicing alpha polypeptide NM_002651 PIK4CBphosphatidylinositol Transferase, Kinase, Golgi stack, 2301 62694-kinase, catalytic, Phosphorylation, Alternative splicing betapolypeptide NM_002653 PITX1 paired-like Homeobox, DNA-binding, 2302 6270homeodomain Developmental protein, Nuclear transcription factor 1protein, Transcription regulation, Activator NM_002654 PKM2 pyruvatekinase, Transferase, Kinase, Glycolysis, 2303 6271 muscle Multigenefamily, Magnesium, Alternative splicing, Hypothetical protein NM_002655PLAG1 pleiomorphic Metal-binding, Zinc, Zinc-finger 2304 6272 adenomagene 1 NM_002659 PLAUR plasminogen Receptor, Signal, Glycoprotein, GPI-2305 6273 activator, urokinase anchor, Repeat, Alternative splicing,receptor Polymorphism, Lipoprotein, Kinase NM_002661 PLCG2 phospholipaseC, Hydrolase, Lipid degradation, 2306 6274 gamma 2 Transducer, SH2domain, SH3 (phosphatidylinositol domain, Repeat, Calcium-binding,specific) Phosphorylation NM_002668 PLP2 proteolipid protein 2Transmembrane, Glycoprotein, 2307 6275 (colonic epithelium- Polymorphismenriched) NM_002676 PMM1 phosphomannomutase 1 Isomerase 2308 6276NM_002685 PMSCL2 polymyositis/scleroderma Hydrolase, Nuclease,Exonuclease, 2309 6277 autoantigen 2, rRNA processing, Nuclear protein,100 kDa RNA-binding, Antigen, Alternative splicing, Hypothetical proteinNM_002686 PNMT phenylethanolamine Transferase, Methyltransferase, 23106278 N-methyltransferase Catecholamine biosynthesis, 3D- structureNM_002688 PNUTL1 peanut-like 1 Hypothetical protein, Cell division, 23116279 (Drosophila) GTP-binding, Coiled coil, Platelet, Transmembrane,Glycoprotein, Hemostasis, Blood coagulation, Signal, Phosphorylation,Cell adhesion, Leucine-rich repeat NM_002691 POLD1 polymerase (DNA DNAreplication, DNA-binding, DNA- 2312 6280 directed), delta 1, directedDNA polymerase, catalytic subunit Transferase, Hydrolase, 125 kDaExonuclease, Zinc-finger, Nuclear protein, Polymorphism NM_002692 POLE2polymerase (DNA Transferase, DNA-directed DNA 2313 6281 directed),epsilon 2 polymerase, DNA replication, DNA- (p59 subunit) binding,Nuclear protein NM_002710 PPP1CC protein phosphatase Hydrolase,Metal-binding, Iron, 2314 6282 1, catalytic subunit, Manganese, Glycogenmetabolism, gamma isoform Multigene family, Cell division, Alternativesplicing, 3D-structure NM_002720 PPP4C protein phosphatase Hydrolase,Metal-binding, Iron, 2315 6283 4 (formerly X), Manganese catalyticsubunit NM_002727 PRG1 proteoglycan 1, Glycoprotein, Proteoglycan,Repeat, 2316 6284 secretory granule Signal NM_002728 PRG2 proteoglycan2, bone Eosinophil, Signal, Immune 2317 6285 marrow (natural killerresponse, Antibiotic, Lectin, cell activator, Proteoglycan,Glycoprotein, Heparin- eosinophil granule binding, 3D-structure majorbasic protein) NM_002731 PRKACB protein kinase, ATP-binding, Kinase,2318 6286 cAMP-dependent, Serine/threonine-protein kinase, catalytic,beta Transferase, Nuclear protein, cAMP, Myristate, Phosphorylation,Multigene family, Lipoprotein NM_002733 PRKAG1 protein kinase, AMP-Fatty acid biosynthesis, Repeat, 2319 6287 activated, gamma 1 CBSdomain, Hypothetical protein non-catalytic subunit NM_002738 PRKCB1protein kinase C, Transferase, Serine/threonine- 2320 6288 beta 1protein kinase, Membrane, ATP- binding, Calcium-binding, Metal- binding,Zinc, Repeat, Phorbol-ester binding, Phosphorylation, Alternativesplicing NM_002741 PRKCL1 protein kinase C-like 1 Transferase,ATP-binding, 2321 6289 Serine/threonine-protein kinase, Phosphorylation,Polymorphism, 3D- structure NM_002745 MAPK1 mitogen-activatedTransferase, Serine/threonine- 2322 6290 protein kinase 1 proteinkinase, ATP-binding, Cell cycle, Phosphorylation, 3D-structure NM_002748MAPK6 mitogen-activated Kinase, Transferase, 2323 6291 protein kinase 6Serine/threonine-protein kinase, ATP-binding, Cell cycle NM_002749 MAPK7mitogen-activated ATP-binding, Kinase, 2324 6292 protein kinase 7Serine/threonine-protein kinase, Transferase, Cell cycle,Phosphorylation, Cell adhesion, Extracellular matrix, Glycoprotein,Calcium, Signal NM_002756 MAP2K3 mitogen-activated Transferase,Serine/threonine- 2325 6293 protein kinase protein kinase,Tyrosine-protein kinase 3 kinase, ATP-binding, Phosphorylation,Alternative splicing, Disease mutation NM_002757 MAP2K5mitogen-activated ATP-binding, Kinase, 2326 6294 protein kinaseSerine/threonine-protein kinase, kinase 5 Transferase NM_002758 MAP2K6mitogen-activated Transferase, Serine/threonine- 2327 6295 proteinkinase protein kinase, Tyrosine-protein kinase 6 kinase, ATP-binding,Phosphorylation, Alternative splicing NM_002764 PRPS1 phosphoribosylNucleotide biosynthesis, 2328 6296 pyrophosphate Transferase, Kinase,Magnesium, synthetase 1 Multigene family, Gout, Disease mutationNM_002765 PRPS2 phosphoribosyl Nucleotide biosynthesis, 2329 6297pyrophosphate Transferase, Kinase, Magnesium, synthetase 2 Multigenefamily NM_002767 PRPSAP2 phosphoribosyl Nucleotide biosynthesis 23306298 pyrophosphate synthetase- associated protein 2 NM_002770 PRSS2protease, serine, 2 Hydrolase, Protease, Serine 2331 6299 (trypsin 2)protease, Digestion, Pancreas, Zymogen, Calcium-binding, Signal,Multigene family NM_002777 PRTN3 proteinase 3 (serine Collagendegradation, Hydrolase, 2332 6300 proteinase, Serine protease, Signal,Zymogen, neutrophil, Wegener Glycoprotein, Polymorphism, 3D-granulomatosis structure autoantigen) NM_002782 PSG6 pregnancy specificImmunoglobulin domain, 2333 6301 beta-1-glycoprotein 6 Glycoprotein,Signal, Multigene family, Repeat, Polymorphism, Alternative splicing,Hypothetical protein, Flavoprotein, Lyase, Thiamine pyrophosphateNM_002786 PSMA1 proteasome Proteasome, Hydrolase, Protease, 2334 6302(prosome, Acetylation, Alternative splicing, macropain) subunit,Threonine protease alpha type, 1 NM_002788 PSMA3 proteasome Proteasome,Hydrolase, Protease, 2335 6303 (prosome, Acetylation, Alternativesplicing, macropain) subunit, Phosphorylation, Threonine protease alphatype, 3 NM_002790 PSMA5 proteasome Proteasome, Hydrolase, Protease, 23366304 (prosome, Threonine protease macropain) subunit, alpha type, 5NM_002793 PSMB1 proteasome Proteasome, Hydrolase, Protease, 2337 6305(prosome, Threonine protease macropain) subunit, beta type, 1 NM_002794PSMB2 proteasome Proteasome, Hydrolase, Protease, 2338 6306 (prosome,Threonine protease macropain) subunit, beta type, 2 NM_002796 PSMB4proteasome Proteasome, Hydrolase, Protease, 2339 6307 (prosome, Zymogen,Polymorphism, Threonine macropain) subunit, protease beta type, 4NM_002805 PSMC5 proteasome ATP-binding, Proteasome 2340 6308 (prosome,macropain) 26S subunit, ATPase, 5 NM_002807 PSMD1 proteasome Proteasome,Repeat 2341 6309 (prosome, macropain) 26S subunit, non- ATPase, 1NM_002809 PSMD3 proteasome Hypothetical protein, Proteasome 2342 6310(prosome, macropain) 26S subunit, non- ATPase, 3 NM_002815 PSMD11proteasome Proteasome 2343 6311 (prosome, macropain) 26S subunit, non-ATPase, 11 NM_002818 PSME2 proteasome Proteasome, Interferon induction2344 6312 (prosome, macropain) activator subunit 2 (PA28 beta) NM_002821PTK7 PTK7 protein ATP-binding, Immunoglobulin 2345 6313 tyrosine kinase7 domain, Receptor, Transferase, Transmembrane, Signal, Glycoprotein,Cell adhesion, Repeat, Hypothetical protein, Kinase, Tyrosine-proteinkinase NM_002824 PTMS parathymosin Hypothetical protein, Immune 23466314 response, Acetylation NM_002826 QSCN6 quiescin Q6 Redox-activecenter 2347 6315 NM_002831 PTPN6 protein tyrosine Hydrolase, SH2 domain,Repeat, 2348 6316 phosphatase, non- Phosphorylation, Alternativesplicing, receptor type 6 3D-structure NM_002842 PTPRH protein tyrosineSignal 2349 6317 phosphatase, receptor type, H NM_002843 PTPRJ proteintyrosine Signal, Glycoprotein, 2350 6318 phosphatase, Transmembrane,Repeat, receptor type, J Hydrolase, Disease mutation, Receptor NM_002850PTPRS protein tyrosine Hydrolase, Receptor, Glycoprotein, 2351 6319phosphatase, Signal, Transmembrane, Cell receptor type, S adhesion,Immunoglobulin domain, Alternative splicing, Repeat NM_002852 PTX3pentaxin-related Pentaxin, Glycoprotein, Signal 2352 6320 gene, rapidlyinduced by IL-1 beta NM_002859 PXN hypothetical protein Cytoskeleton,Phosphorylation, LIM 2353 6321 FLJ23042 domain, Repeat, Metal-binding,Zinc, Alternative splicing, 3D-structure, Hypothetical protein NM_002862PYGB phosphorylase, Carbohydrate metabolism, 2354 6322 glycogen; brainGlycosyltransferase, Pyridoxal phosphate, Transferase, Glycogenmetabolism, Allosteric enzyme, Phosphorylation NM_002863 PYGLphosphorylase, Transferase, Glycosyltransferase, 2355 6323 glycogen;liver (Hers Carbohydrate metabolism, Glycogen disease, glycogenmetabolism, Allosteric enzyme, storage disease type Pyridoxal phosphate,VI) Phosphorylation, Glycogen storage disease, Disease mutation,Polymorphism, 3D-structure NM_002865 RAB2 RAB2, member RAS GTP-binding,Transport, Protein 2356 6324 oncogene family transport, Endoplasmicreticulum, Golgi stack, Lipoprotein, Prenylation NM_002872 RAC2ras-related C3 GTP-binding, Prenylation, 2357 6325 botulinum toxinLipoprotein, 3D-structure substrate 2 (rho family, small GTP bindingprotein Rac2) NM_002878 RAD51L3 RAD51-like 3 (S. cerevisiae) DNA damage,DNA repair, DNA 2358 6326 recombination, DNA-binding, ATP- binding,Nuclear protein, Alternative splicing, Hypothetical protein NM_002880RAF1 v-raf-1 murine Hypothetical protein, Metal-binding, 2359 6327leukemia viral Zinc, Zinc-finger, Transferase, oncogene homolog 1Serine/threonine-protein kinase, Proto-oncogene, ATP-binding,Phorbol-ester binding, Phosphorylation, 3D-structure, Repeat NM_002881RALB v-ral simian GTP-binding, Prenylation, 2360 6328 leukemia viralLipoprotein oncogene homolog B (ras related; GTP binding protein)NM_002883 RANGAP1 Ran GTPase Hypothetical protein, GTPase 2361 6329activating protein 1 activation, Repeat, Leucine-rich repeat, Ublconjugation NM_002887 RARS arginyl-tRNA Aminoacyl-tRNA synthetase,Protein 2362 6330 synthetase biosynthesis, Ligase, ATP-binding,Alternative initiation NM_002893 RBBP7 retinoblastoma Nuclear protein,Repeat, WD repeat 2363 6331 binding protein 7 NM_002896 RBM4 RNA bindingmotif Zinc-finger 2364 6332 protein 4 NM_002897 RBMS1 RNA binding motif,DNA-binding, DNA replication, RNA- 2365 6333 single stranded binding,Nuclear protein, interacting protein 1 Phosphorylation NM_002901 RCN1reticulocalbin 1, EF- Calcium-binding, Endoplasmic 2366 6334 handcalcium reticulum, Signal, Glycoprotein, binding domain Repeat,Polymorphism NM_002902 RCN2 reticulocalbin 2, EF- Calcium-binding,Endoplasmic 2367 6335 hand calcium reticulum, Signal, Repeat bindingdomain NM_002903 RCV1 recoverin Calcium-binding, Repeat, Myristate, 23686336 Vision, Lipoprotein NM_002905 RDH5 retinol Oxidoreductase, NAD,Membrane, 2369 6337 dehydrogenase 5 Vision, Disease mutation, (11-cisand 9-cis) Polymorphism NM_002910 RENBP renin binding protein Isomerase2370 6338 NM_002918 RFX1 regulatory factor X, 1 DNA-binding,Transcription 2371 6339 (influences HLA regulation, Activator, Nuclearclass II expression) protein, 3D-structure NM_002922 RGS1 regulator ofG- Signal transduction inhibitor, B-cell 2372 6340 protein signalling 1activation, Phosphorylation NM_002923 RGS2 regulator of G- Signaltransduction inhibitor, Cell 2373 6341 protein signalling 2, cycle,Phosphorylation 24 kDa NM_002934 RNASE2 ribonuclease, RNase Hydrolase,Nuclease, Endonuclease, 2374 6342 A family, 2 (liver, Chemotaxis,Eosinophil, eosinophil-derived Glycoprotein, Signal, Polymorphism,neurotoxin) 3D-structure NM_002935 RNASE3 ribonuclease, RNase Hydrolase,Nuclease, Endonuclease, 2375 6343 A family, 3 Eosinophil, Glycoprotein,Antibiotic, (eosinophil cationic Signal, Polymorphism, 3D-structureprotein) NM_002936 RNASEH1 ribonuclease H1 Hydrolase, Nuclease,Endonuclease, 2376 6344 Magnesium NM_002939 RNH ribonuclease/angiogeninRepeat, Leucine-rich repeat, 3D- 2377 6345 inhibitor structure,Polymorphism, Hypothetical protein NM_002940 ABCE1 ATP-binding Capsidassembly, Chaperone, 2378 6346 cassette, sub-family Mitochondrion,ATP-binding, Repeat E (OABP), member 1 NM_002953 RPS6KA1 ribosomalprotein S6 Transferase, Serine/threonine- 2379 6347 kinase, 90 kDa,protein kinase, ATP-binding, Repeat, polypeptide 1 Multigene familyNM_002957 RXRA retinoid X receptor, Receptor, Transcription regulation,2380 6348 alpha DNA-binding, Nuclear protein, Zinc- finger, Multigenefamily, 3D- structure, Polymorphism NM_002961 S100A4 S100 calciumCalcium-binding, 3D-structure 2381 6349 binding protein A4 (calciumprotein, calvasculin, metastasin, murine placental homolog) NM_002964S100A8 S100 calcium Macrophage, Calcium-binding, 3D- 2382 6350 bindingprotein A8 structure (calgranulin A) NM_002965 S100A9 S100 calciumCalcium-binding, Macrophage, 2383 6351 binding protein A9Phosphorylation, Polymorphism, 3D- (calgranulin B) structure NM_002967SAFB scaffold attachment Transcription regulation, Repressor, 2384 6352factor B Nuclear protein, DNA-binding, RNA- binding, PhosphorylationNM_002969 MAPK12 mitogen-activated Transferase, Serine/threonine- 23856353 protein kinase 12 protein kinase, ATP-binding, Cell cycle,Phosphorylation, Polymorphism, 3D-structure NM_002978 SCNN1D sodiumchannel, Ion transport, Sodium transport, 2386 6354 nonvoltage-gated 1,Ionic channel, Transmembrane, delta Glycoprotein, Alternative splicing,Sodium channel NM_002984 CCL4 chemokine (C-C Cytokine, Chemotaxis,Inflammatory 2387 6355 motif) ligand 4 response, Signal, 3D-structureNM_002985 CCL5 chemokine (C-C Cytokine, Chemotaxis, T-cell, Signal, 23886356 motif) ligand 5 Inflammatory response, 3D-structure NM_003003SEC14L1 SEC14-like 1 (S. cerevisiae) 2389 6357 NM_003006 SELPLG selectinP ligand Hypothetical protein, Cell adhesion, 2390 6358 Glycoprotein,Transmembrane, Signal, Repeat, Polymorphism, Sulfation, 3D-structure,Lectin, Selectin NM_003011 SET SET translocation Proto-oncogene,Chromosomal 2391 6359 (myeloid leukemia- translocation, Nuclear protein,associated) Phosphorylation NM_003021 SGT small glutamine-richChaperone, Repeat, TPR repeat, 2392 6360 tetratricopeptide Hypotheticalprotein repeat (TPR)- containing, alpha NM_003040 SLC4A2 solute carrierfamily Transmembrane, Glycoprotein, 2393 6361 4, anion exchanger,Transport, Antiport, Ion transport, member 2 Anion exchange,Lipoprotein, (erythrocyte Palmitate, Alternative splicing membraneprotein band 3-like 1) NM_003044 SLC6A12 solute carrier familyNeurotransmitter transport, 2394 6362 6 (neurotransmitter Transport,Transmembrane, transporter, Glycoprotein, Symport betaine/GABA), member12 NM_003055 SLC18A3 choline Transport, Neurotransmitter 2395 6363acetyltransferase transport, Transmembrane, Glycoprotein NM_003056SLC19A1 solute carrier family Folate-binding, Transport, 2396 6364 19(folate Transmembrane, Glycoprotein transporter), member 1 NM_003057SLC22A1 solute carrier family Transmembrane 2397 6365 22 (organic cationtransporter), member 1 NM_003059 SLC22A4 solute carrier familyTransmembrane 2398 6366 22 (organic cation transporter), member 4NM_003064 SLPI secretory leukocyte Serine protease inhibitor, Repeat,2399 6367 protease inhibitor Signal (antileukoproteinase) NM_003066 SLPIsecretory leukocyte Serine protease inhibitor, Repeat, 2400 6368protease inhibitor Signal (antileukoproteinase) NM_003071 SMARCA3SWI/SNF related, ATP-binding, DNA-binding, Helicase, 2401 6369 matrixassociated, Hydrolase, Metal-binding, Zinc, Zinc- actin dependent fingerregulator of chromatin, subfamily a, member 3 NM_003073 SMARCB1 SWI/SNFrelated, Hypothetical protein, Transcription 2402 6370 matrixassociated, regulation, Activator, Nuclear actin dependent protein,Alternative splicing, Anti- regulator of oncogene chromatin, subfamilyb, member 1 NM_003074 SMARCC1 SWI/SNF related, DNA-binding, Nuclearprotein 2403 6371 matrix associated, actin dependent regulator ofchromatin, subfamily c, member 1 NM_003077 SMARCD2 SWI/SNF related, 24046372 matrix associated, actin dependent regulator of chromatin,subfamily d, member 2 NM_003079 SMARCE1 SWI/SNF related, 2405 6373matrix associated, actin dependent regulator of chromatin, subfamily e,member 1 NM_003084 SNAPC3 small nuclear RNA Hypothetical protein,Transcription 2406 6374 activating complex, regulation, DNA-bindingpolypeptide 3, 50 kDa NM_003085 SNCB synuclein, beta Phosphorylation,Repeat 2407 6375 NM_003086 SNAPC4 small nuclear RNA DNA-binding, Nuclearprotein, 2408 6376 activating complex, Hypothetical protein polypeptide4, 190 kDa NM_003088 FSCN1 fascin homolog 1, Actin-binding, Acetylation,2409 6377 actin-bundling Phosphorylation, 3D-structure, proteinHypothetical protein (Strongylocentrotus purpuratus) NM_003090 SNRPA1small nuclear Nuclear protein, RNA-binding, 2410 6378 ribonucleoproteinRibonucleoprotein, Leucine-rich polypeptide A′ repeat, Repeat,3D-structure NM_003092 SNRPB2 small nuclear mRNA processing, mRNAsplicing, 2411 6379 ribonucleoprotein Nuclear protein, RNA-binding,polypeptide B″ Ribonucleoprotein, Repeat, Systemic lupus erythematosus,3D- structure NM_003093 SNRPC small nuclear Nuclear protein,RNA-binding, 2412 6380 ribonucleoprotein Ribonucleoprotein, Zinc-fingerpolypeptide C NM_003094 SNRPE small nuclear Nuclear protein,Ribonucleoprotein, 2413 6381 ribonucleoprotein Systemic lupuserythematosus, polypeptide E mRNA splicing, mRNA processing, RNA-bindingNM_003100 SNX2 sorting nexin 2 Transport, Protein transport 2414 6382NM_003104 SORD sorbitol Oxidoreductase, Zinc, Metal-binding, 2415 6383dehydrogenase NAD, Acetylation, Polymorphism NM_003105 SORL1sortilin-related Endocytosis, Receptor, 2416 6384 receptor, L(DLRTransmembrane, EGF-like domain, class) A repeats- Repeat, Glycoprotein,LDL, Lipid containing transport, Cholesterol metabolism, SignalNM_003107 SOX4 SRY (sex DNA-binding, Nuclear protein, 2417 6385determining region Transcription regulation, Activator Y)-box 4NM_003120 SPI1 spleen focus forming Proto-oncogene, DNA-binding, 24186386 virus (SFFV) proviral Transcription regulation, Activator,integration oncogene Nuclear protein spi1 NM_003135 SRP19 signalrecognition Signal recognition particle, RNA- 2419 6387 particle 19 kDabinding, Ribonucleoprotein, 3D- structure NM_003141 SSA1 Sjogrensyndrome Systemic lupus erythematosus, Zinc- 2420 6388 antigen A1 (52kDa, finger, Antigen, RNA-binding, ribonucleoprotein Ribonucleoprotein,DNA-binding, autoantigen SS- Polymorphism A/Ro) NM_003143 SSBP1single-stranded DNA DNA-binding, DNA replication, 2421 6389 bindingprotein 1 Mitochondrion, Transit peptide, 3D- structure NM_003146 SSRP1structure specific DNA-binding, Nuclear protein 2422 6390 recognitionprotein 1 NM_003150 STAT3 signal transducer Hypothetical protein,Transcription 2423 6391 and activator of regulation, Activator,DNA-binding, transcription 3 Nuclear protein, Phosphorylation,(acute-phase SH2 domain response factor) NM_003153 STAT6 signaltransducer Transcription regulation, Repressor, 2424 6392 and activatorof Alternative splicing, Activator, DNA- transcription 6, binding,Nuclear protein, interleukin-4 induced Phosphorylation, SH2 domain,Polymorphism NM_003163 STX1B1 Human mRNA for Neurotransmitter transport,Coiled 2425 6393 SYNTAXIN1B, coil, Transmembrane complete cds. NM_003168SUPT4H1 suppressor of Ty 4 Nuclear protein, Transcription, Zinc- 24266394 homolog 1 (S. cerevisiae) finger NM_003169 SUPT5H suppressor of Ty5 2427 6395 homolog (S. cerevisiae) NM_003171 SUPV3L1 suppressor ofvar1, ATP-binding, Helicase, Hydrolase 2428 6396 3-like 1 (S.cerevisiae) NM_003174 SVIL supervillin 2429 6397 NM_003177 SYK spleentyrosine Transferase, Tyrosine-protein 2430 6398 kinase kinase,ATP-binding, Phosphorylation, SH2 domain, Repeat, Alternative splicing,3D- structure NM_003190 TAPBP TAP binding protein Immunoglobulin domain,Signal, 2431 6399 (tapasin) Transmembrane, Endoplasmic reticulum,Microsome, Alternative splicing, Polymorphism NM_003191 TARShypothetical protein Aminoacyl-tRNA synthetase, Protein 2432 6400MGC9344 biosynthesis, Ligase, ATP-binding NM_003193 TBCEtubulin-specific 2433 6401 chaperone e NM_003197 TCEB1L S-phase kinase-Ubl conjugation pathway, Alternative 2434 6402 associated proteinsplicing, 3D-structure 1A (p19A) NM_003199 TCF4 transcription factor 4Transcription regulation, DNA- 2435 6403 binding, Activator, Nuclearprotein, Alternative splicing NM_003201 TFAM transcription factorTranscription regulation, DNA- 2436 6404 A, mitochondrial binding,Activator, Mitochondrion, Transit peptide, Repeat, PolymorphismNM_003202 TCF7 transcription factor 7 Transcription regulation,Activator, 2437 6405 (T-cell specific, Repressor, Trans-acting factor,HMG-box) Nuclear protein, DNA-binding, Wnt signaling pathway,Alternative splicing, Alternative promoter usage NM_003203 C2orf3chromosome 2 open 2438 6406 reading frame 3 NM_003205 TCF12transcription factor Transcription regulation, DNA- 2439 6407 12 (HTF4,helix- binding, Nuclear protein, loop-helix Developmental proteintranscription factors 4) NM_003217 TEGT testis enhanced Apoptosis,Transmembrane 2440 6408 gene transcript (BAX inhibitor 1) NM_003226 TFF3trefoil factor 3 Signal, 3D-structure 2441 6409 (intestinal) NM_003227TFR2 transferrin receptor 2 Transmembrane, Glycoprotein, 2442 6410Receptor, Signal-anchor, Alternative splicing, Disease mutationNM_003236 TGFA transforming growth EGF-like domain, Growth factor, 24436411 factor, alpha Mitogen, Glycoprotein, Transmembrane, Signal, 3D-structure, Lipoprotein, Palmitate NM_003245 TGM3 transglutaminase 3Transferase, Acyltransferase, 2444 6412 (E polypeptide, Calcium-binding,Zymogen, protein-glutamine- Keratinization, 3D-structure gamma-glutamyltransferase) NM_003248 THBS4 thrombospondin 4 Glycoprotein, Celladhesion, 2445 6413 Calcium-binding, Repeat, EGF-like domain, SignalNM_003252 TIAL1 TIA1 cytotoxic RNA-binding, Apoptosis, Repeat 2446 6414granule-associated RNA binding protein- like 1 NM_003255 TIMP2 tissueinhibitor of Hypothetical protein, 2447 6415 metalloproteinase 2Metalloprotease inhibitor, Signal, 3D- structure NM_003263 TLR1toll-like receptor 1 Receptor, Immune response, 2448 6416 Inflammatoryresponse, Signal, Transmembrane, Repeat, Leucine- rich repeat,Glycoprotein, 3D- structure NM_003274 TMEM1 transmembrane Transport,Endoplasmic reticulum, 2449 6417 protein 1 Golgi stack, PolymorphismNM_003281 TNNI1 troponin I, skeletal, Muscle protein, Actin-binding, Ubl2450 6418 slow conjugation pathway, Hydrolase, Thiol protease, Multigenefamily NM_003288 TPD52L2 tumor protein D52- Coiled coil, Alternativesplicing 2451 6419 like 2 NM_003289 TPM2 tropomyosin 2 (beta) Muscleprotein, Cytoskeleton, Actin- 2452 6420 binding, Coiled coil,Alternative splicing, Multigene family, Acetylation, Disease mutationNM_003290 TPM4 tropomyosin 4 Muscle protein, Cytoskeleton, Actin- 24536421 binding, Coiled coil, Alternative splicing, Multigene familyNM_003299 TRA1 tumor rejection Chaperone, Endoplasmic reticulum, 24546422 antigen (gp96) 1 Glycoprotein, Calcium-binding, Signal NM_003307TRPM2 Homo sapiens Ionic channel, Transmembrane, Ion 2455 6423 transientreceptor transport, Calcium channel, potential cation Alternativesplicing channel, subfamily M, member 2 (TRPM2), mRNA. NM_003310 TSSC1tumor suppressing Repeat, WD repeat 2456 6424 subtransferable candidate1 NM_003316 TTC3 tetratricopeptide Metal-binding, Zinc, Zinc-finger,2457 6425 repeat domain 3 Repeat, TPR repeat, Alternative splicing,Polymorphism NM_003326 TNFSF4 tumor necrosis factor Cytokine,Transmembrane, 2458 6426 (ligand) superfamily, Glycoprotein,Signal-anchor member 4 (tax- transcriptionally activated glycoprotein 1,34 kDa) NM_003329 TXN thioredoxin Redox-active center, Electron 24596427 transport, 3D-structure NM_003330 TXNRD1 thioredoxin Redox-activecenter, 2460 6428 reductase 1 Oxidoreductase, NADP, Flavoprotein, FADNM_003331 TYK2 tyrosine kinase 2 Transferase, Tyrosine-protein 2461 6429kinase, ATP-binding, Phosphorylation, SH2 domain, Repeat NM_003332TYROBP TYRO protein Transmembrane, Signal, 2462 6430 tyrosine kinasePhosphorylation, Polymorphism, binding protein Receptor NM_003338 UBE2D1ubiquitin-conjugating Ubl conjugation pathway, Ligase, 2463 6431 enzymeE2D 1 Multigene family (UBC4/5 homolog, yeast) NM_003341 UBE2E1ubiquitin-conjugating Ubl conjugation pathway, Ligase, 2464 6432 enzymeE2E 1 Multigene family (UBC4/5 homolog, yeast) NM_003343 UBE2G2ubiquitin-conjugating Ubl conjugation pathway, Ligase, 2465 6433 enzymeE2G 2 Multigene family, Hypothetical (UBC7 homolog, protein yeast)NM_003348 UBE2N ubiquitin-conjugating Ubl conjugation pathway, Ligase,2466 6434 enzyme E2N Multigene family, 3D-structure (UBC13 homolog,yeast) NM_003355 UCP2 uncoupling protein 2 Mitochondrion, Innermembrane, 2467 6435 (mitochondrial, Repeat, Transmembrane, Transport,proton carrier) Polymorphism NM_003358 UGCG UDP-glucose Transferase,Glycosyltransferase, 2468 6436 ceramide Transmembrane, Signal-anchor,glucosyltransferase Endoplasmic reticulum NM_003362 UNG uracil-DNA DNArepair, Hydrolase, Glycosidase, 2469 6437 glycosylase Nuclear protein,Mitochondrion, Transit peptide, Disease mutation, Alternative splicing,3D-structure NM_003364 UP uridine Transferase, Glycosyltransferase, 24706438 phosphorylase 1 Alternative splicing NM_003366 UQCRC2 ubiquinol-Mitochondrion, Inner membrane, 2471 6439 cytochrome c Electrontransport, Respiratory reductase core chain, Oxidoreductase, Transitprotein II peptide NM_003370 VASP vasodilator- Phosphorylation,Actin-binding, 3D- 2472 6440 stimulated structure phosphoproteinNM_003374 VDAC1 voltage-dependent Outer membrane, Porin, 2473 6441 anionchannel 1 Mitochondrion, Acetylation NM_003375 VDAC2 voltage-dependentOuter membrane, Porin, 2474 6442 anion channel 2 Mitochondrion,Alternative splicing, Polymorphism NM_003377 VEGFB vascular endothelialMitogen, Growth factor, 2475 6443 growth factor B Glycoprotein, Signal,Heparin- binding, Alternative splicing, Multigene family NM_003387WASPIP Wiskott-Aldrich Actin-binding, Repeat, 2476 6444 syndrome proteinPolymorphism interacting protein NM_003389 CORO2A coronin, actinActin-binding, Repeat, WD repeat, 2477 6445 binding protein, 2A Coiledcoil NM_003403 YY1 YY1 transcription Transcription regulation,Repressor, 2478 6446 factor Activator, Nuclear protein, Zinc- finger,Metal-binding, DNA-binding, Repeat, 3D-structure NM_003407 ZFP36 zincfinger protein Nuclear protein, Repeat, Metal- 2479 6447 36, C3H type,binding, Zinc-finger, DNA-binding homolog (mouse) NM_003426 ZNF74 zincfinger protein 74 Transcription regulation, DNA- 2480 6448 (Cos52)binding, RNA-binding, Zinc-finger, Metal-binding, Nuclear protein,Repeat, Alternative splicing, Polymorphism NM_003451 ZNF177 zinc fingerprotein Transcription regulation, DNA- 2481 6449 177 binding,Zinc-finger, Metal-binding, Nuclear protein, Repeat, Hypotheticalprotein NM_003457 ZNF207 zinc finger protein Zinc-finger, Metal-binding,DNA- 2482 6450 207 binding, Nuclear protein, Alternative splicing,Hypothetical protein NM_003461 ZYX zyxin LIM domain, Metal-binding,Zinc, 2483 6451 Repeat, Cell adhesion, Receptor NM_003465 CHIT1chitinase 1 Carbohydrate metabolism, Chitin 2484 6452 (chitotriosidase)degradation, Polysaccharide degradation, Hydrolase, Glycosidase,Chitin-binding, Signal, Alternative splicing, 3D-structure NM_003466PAX8 paired box gene 8 DNA-binding, Developmental 2485 6453 protein,Nuclear protein, Paired box, Transcription, Transcription regulation,Differentiation, Alternative splicing, Disease mutation, PolymorphismNM_003467 CXCR4 chemokine (C—X—C G-protein coupled receptor, 2486 6454motif) receptor 4 Receptor, Transmembrane, Glycoprotein, Sulfation,Antigen, Alternative splicing NM_003475 C11orf13 chromosome 11 Coiledcoil, Alternative splicing 2487 6455 open reading frame 13 NM_003477PDX1 pyruvate Transit peptide, Mitochondrion, 2488 6456 dehydrogenaseLipoyl, Hypothetical protein, complex, component X Acyltransferase,Transferase NM_003489 NRIP1 nuclear receptor Transcription regulation,Nuclear 2489 6457 interacting protein 1 protein NM_003493 HIST3H3histone 3, H3 Nuclear protein, Chromosomal 2490 6458 protein,DNA-binding, Nucleosome core, Multigene family, Acetylation, MethylationNM_003494 DYSF dysferlin, limb girdle Transmembrane, Repeat, Disease2491 6459 muscular dystrophy mutation, Hypothetical protein 2B(autosomal recessive) NM_003498 SNN stannin Transmembrane, Hypothetical2492 6460 protein NM_003507 FZD7 frizzled homolog 7 Multigene family,G-protein coupled 2493 6461 (Drosophila) receptor, Transmembrane,Developmental protein, Wnt signaling pathway, Glycoprotein, SignalNM_003508 FZD9 frizzled homolog 9 Multigene family, G-protein coupled2494 6462 (Drosophila) receptor, Transmembrane, Developmental protein,Wnt signaling pathway, Glycoprotein, Signal NM_003530 HIST1H3D histone1, H3d Nuclear protein, Chromosomal 2495 6463 protein, DNA-binding,Nucleosome core, Multigene family, Acetylation, Methylation NM_003532HIST1H3E histone 1, H3c Nuclear protein, Chromosomal 2496 6464 protein,DNA-binding, Nucleosome core, Multigene family, Acetylation, MethylationNM_003534 HIST1H3G histone 1, H3g Nuclear protein, Chromosomal 2497 6465protein, DNA-binding, Nucleosome core, Multigene family, Acetylation,Methylation NM_003535 HIST1H3J histone 1, H3j Nuclear protein,Chromosomal 2498 6466 protein, DNA-binding, Nucleosome core, Multigenefamily, Acetylation, Methylation NM_003549 HYAL3hyaluronoglucosaminidase 3 EGF-like domain 2499 6467 NM_003560 PLA2G6phospholipase A2, Hypothetical protein, ANK repeat, 2500 6468 group VI(cytosolic, Repeat, Hydrolase, Lipid calcium- degradation, Membrane,Alternative independent) splicing NM_003562 SLC25A11 solute carrierfamily Mitochondrion, Inner membrane, 2501 6469 25 (mitochondrialRepeat, Transmembrane, Transport carrier; oxoglutarate carrier), member11 NM_003565 ULK1 unc-51-like kinase 1 Hypothetical protein,ATP-binding, 2502 6470 (C. elegans) Transferase, Serine/threonine-protein kinase NM_003570 CMAH MRNA for CMP-N- 2503 6471 acetylneuraminicacid hydroxylase, complete cds. NM_003577 UTF1 undifferentiated 25046472 embryonic cell transcription factor 1 NM_003579 RAD54L RAD54-like(S. cerevisiae) ATP-binding, DNA repair, Helicase, 2505 6473 HydrolaseNM_003587 DDX16 DEAH (Asp-Glu-Ala- ATP-binding, Helicase, Hydrolase,2506 6474 His) box polypeptide mRNA processing, mRNA splicing, 16Nuclear protein NM_003599 SUPT3H suppressor of Ty 3 Transcriptionregulation, Activator, 2507 6475 homolog (S. cerevisiae) Nuclearprotein, Alternative splicing NM_003601 SMARCA5 SWI/SNF related,ATP-binding, DNA-binding, Helicase, 2508 6476 matrix associated,Hydrolase, Nuclear protein actin dependent regulator of chromatin,subfamily a, member 5 NM_003618 MAP4K3 mitogen-activated ATP-binding,Kinase, Transferase 2509 6477 protein kinase kinase kinase kinase 3NM_003624 RANBP3 RAN binding protein 3 Hypothetical protein 2510 6478NM_003634 NIPSNAP1 nipsnap homolog 1 Polymorphism 2511 6479 (C. elegans)NM_003635 NDST2 N-deacetylase/N- Hypothetical protein, Transferase, 25126480 sulfotransferase Transmembrane, Glycoprotein, Golgi (heparan stack,Signal-anchor glucosaminyl) 2 NM_003636 KCNAB2 potassium voltage- Ionicchannel, Ion transport, 2513 6481 gated channel, Potassium transport,Voltage-gated shaker-related channel, Alternative splicing subfamily,beta member 2 NM_003639 IKBKG inhibitor of kappa Coiled coil,Transcription regulation, 2514 6482 light polypeptide Nuclear protein,Disease mutation, gene enhancer in B- Anhidrotic ectodermal dysplasia,cells, kinase gamma Repeat, LIM domain, Metal-binding, Zinc,Developmental protein, Differentiation, Zinc-finger NM_003644 GAS7growth arrest- Neurogenesis, Developmental 2515 6483 specific 7 protein,Coiled coil, Proto-oncogene, Chromosomal translocation, Alternativesplicing NM_003648 DGKD diacylglycerol Transferase, Kinase,Phorbol-ester 2516 6484 kinase, delta 130 kDa binding, Repeat, Multigenefamily NM_003650 CST7 cystatin F Thiol protease inhibitor, 2517 6485(leukocystatin) Glycoprotein, Signal NM_003655 CBX4 chromobox homologChromatin regulator, Nuclear 2518 6486 4 (Pc class homolog, protein,Transcription regulation, Drosophila) Repressor, Alternative splicingNM_003668 MAPKAPK5 mitogen-activated Hypothetical protein, ATP-binding,2519 6487 protein kinase- Kinase, Serine/threonine-protein activatedprotein kinase, Transferase kinase 5 NM_003674 CDK10 cyclin-dependentTransferase, Serine/threonine- 2520 6488 kinase (CDC2-like) proteinkinase, ATP-binding, Kinase, 10 Cyclin NM_003680 YARS tyrosyl-tRNAAminoacyl-tRNA synthetase, Protein 2521 6489 synthetase biosynthesis,Ligase, ATP-binding, RNA-binding, tRNA-binding, 3D- structure NM_003681PDXK pyridoxal Transferase, Kinase, Alternative 2522 6490 (pyridoxine,vitamin splicing B6) kinase NM_003682 MADD MAP-kinase Hypotheticalprotein, Kinase 2523 6491 activating death domain NM_003685 KHSRPKH-type splicing Transport, mRNA transport, mRNA 2524 6492 regulatoryprotein processing, mRNA splicing, (FUSE binding Transcriptionregulation, Trans- protein 2) acting factor, Nuclear protein, DNA-binding, RNA-binding, Repeat NM_003686 EXO1 exonuclease 1 Exonuclease,Hypothetical protein 2525 6493 NM_003690 PRKRA protein kinase,Hypothetical protein, Kinase 2526 6494 interferon-inducible doublestranded RNA dependent activator NM_003707 RUVBL1 RuvB-like 1 (E. coli)Transcription, DNA recombination, 2527 6495 ATP-binding, Hydrolase,Helicase, Nuclear protein NM_003709 KLF7 Kruppel-like factor 7Transcription regulation, Activator, 2528 6496 (ubiquitous) Zinc-finger,Metal-binding, DNA- binding, Nuclear protein, Repeat NM_003713 PPAP2Bphosphatidic acid Collagen, Hydrolase, Hypothetical 2529 6497phosphatase type protein 2B NM_003725 RODH 3-hydroxysteroidOxidoreductase 2530 6498 epimerase NM_003726 SCAP1 src family associatedSH3 domain 2531 6499 phosphoprotein 1 NM_003730 RNASE6PL ribonuclease T2Hydrolase, Nuclease, Endonuclease, 2532 6500 Glycoprotein, Signal,Alternative splicing, Polymorphism, Hypothetical protein NM_003734 AOC3amine oxidase, Oxidoreductase, Copper, TPQ, 2533 6501 copper containing3 Glycoprotein, Transmembrane, (vascular adhesion Signal-anchor, Celladhesion, protein 1) Polymorphism, Metal-binding NM_003748 ALDH4A1aldehyde Oxidoreductase, NAD, Proline 2534 6502 dehydrogenase 4metabolism, Mitochondrion, Transit family, member A1 peptide,Polymorphism, Disease mutation NM_003750 EIF3S10 eukaryotic Initiationfactor, Protein biosynthesis, 2535 6503 translation initiation Repeat,Phosphorylation factor 3, subunit 10 theta, 150/170 kDa NM_003754 EIF3S5eukaryotic Initiation factor, Protein biosynthesis, 2536 6504translation initiation Polymorphism, Hypothetical protein factor 3,subunit 5 epsilon, 47 kDa NM_003755 EIF3S4 eukaryotic Initiation factor,Protein biosynthesis, 2537 6505 translation initiation RNA-bindingfactor 3, subunit 4 delta, 44 kDa NM_003756 EIF3S3 eukaryotic Initiationfactor, Protein biosynthesis 2538 6506 translation initiation factor 3,subunit 3 gamma, 40 kDa NM_003758 EIF3S1 eukaryotic Hypotheticalprotein, Initiation factor, 2539 6507 translation initiation Proteinbiosynthesis factor 3, subunit 1 alpha, 35 kDa NM_003764 STX11 syntaxin11 Coiled coil, Membrane, 2540 6508 Polymorphism NM_003765 STX10syntaxin 10 Coiled coil, Transmembrane, 2541 6509 Transport, Proteintransport, Golgi stack, Alternative splicing NM_003769 SFRS9 splicingfactor, Nuclear protein, RNA-binding, 2542 6510 arginine/serine-rich 9mRNA splicing, Repeat, Phosphorylation NM_003776 MRPL40 mitochondrialRibosomal protein, Mitochondrion, 2543 6511 ribosomal protein Transitpeptide, Polymorphism L40 NM_003782 B3GALT4 UDP- Transferase,Glycosyltransferase, 2544 6512 Gal:betaGlcNAc Glycoprotein,Transmembrane, beta 1,3- Signal-anchor, Golgi stackgalactosyltransferase, polypeptide 4 NM_003786 ABCC3 ATP-bindingATP-binding, Glycoprotein, 2545 6513 cassette, sub-family Transmembrane,Transport, Repeat, C (CFTR/MRP), Alternative splicing member 3 NM_003791MBTPS1 membrane-bound Hydrolase, Protease, Serine 2546 6514transcription factor protease, Lipid metabolism, protease, site 1Cholesterol metabolism, Signal, Transmembrane, Endoplasmic reticulum,Golgi stack, Zymogen, Autocatalytic cleavage, Glycoprotein, CalciumNM_003796 C19orf2 chromosome 19 Nuclear protein 2547 6515 open readingframe 2 NM_003801 GPAA1 GPAA1P anchor Hypothetical protein 2548 6516attachment protein 1 homolog (yeast) NM_003805 CRADD CASP2 and RIPK1Apoptosis, 3D-structure 2549 6517 domain containing adaptor with deathdomain NM_003807 TNFSF14 tumor necrosis factor Cytokine, Transmembrane,2550 6518 (ligand) superfamily, Glycoprotein, Signal-anchor, member 14Alternative splicing NM_003808 TNFSF13 tumor necrosis factor Cytokine,Immune response, 2551 6519 (ligand) superfamily, Glycoprotein,Alternative splicing member 13 NM_003815 ADAM15 a disintegrin andHydrolase, Metalloprotease, Zinc, 2552 6520 metalloproteinase Signal,Glycoprotein, Zymogen, domain 15 Transmembrane, EGF-like domain,(metargidin) SH3-binding, Phosphorylation NM_003820 TNFRSF14 tumornecrosis factor Receptor, Transmembrane, 2553 6521 receptor superfamily,Glycoprotein, Repeat, Signal, member 14 Polymorphism, 3D-structure(herpesvirus entry mediator) NM_003829 MPDZ multiple PDZ domainHypothetical protein 2554 6522 protein NM_003830 SIGLEC5 sialic acidbinding Ig- Cell adhesion, Lectin, 2555 6523 like lectin 5Transmembrane, Signal, Glycoprotein, Immunoglobulin domain, Repeat,Antigen, Polymorphism NM_003841 TNFRSF10C tumor necrosis factorReceptor, Apoptosis, Glycoprotein, 2556 6524 receptor superfamily,Repeat, GPI-anchor, Signal, member 10c, decoy Lipoprotein without anintracellular domain NM_003846 PEX11B peroxisomal 2557 6525 biogenesisfactor 11B NM_003852 TIF1 transcriptional Elongation factor, Protein2558 6526 intermediary factor 1 biosynthesis, GTP-binding, Methylation,Multigene family, Transcription regulation, Repressor, DNA-binding,Bromodomain, Zinc- finger, Alternative splicing, Nuclear protein, Coiledcoil, Repeat NM_003853 IL18RAP interleukin 18 Receptor 2559 6527receptor accessory protein NM_003866 INPP4B inositol Hypotheticalprotein 2560 6528 polyphosphate-4- phosphatase, type II, 105 kDaNM_003877 SOCS2 suppressor of SH2 domain, Growth regulation, 2561 6529cytokine signaling 2 Signal transduction inhibitor NM_003887 DDEF2development and Hypothetical protein, ANK repeat, 2562 6530differentiation Repeat, SH3 domain enhancing factor 2 NM_003893 LDB1 LIMdomain binding 1 DNA-binding, Homeobox, Nuclear 2563 6531 proteinNM_003895 SYNJ1 synaptojanin 1 Hydrolase, Alternative splicing, 25646532 Repeat, Endocytosis, RNA-binding, Multigene family, Hypotheticalprotein NM_003896 SIAT9 sialyltransferase 9 Transferase,Glycosyltransferase, 2565 6533 (CMP- Glycoprotein, Transmembrane,NeuAc:lactosylceramide Signal-anchor, Golgi stack alpha-2,3-sialyltransferase; GM3 synthase) NM_003897 IER3 immediate earlyGlycoprotein, Transmembrane, 2566 6534 response 3 Signal-anchorNM_003899 ARHGEF7 Rho guanine Hypothetical protein, SH3 domain, 25676535 nucleotide exchange Guanine-nucleotide releasing factor, factor(GEF) 7 Alternative splicing, 3D-structure NM_003900 SQSTM1 sequestosome1 Hypothetical protein 2568 6536 NM_003903 CDC16 CDC16 cell division Ublconjugation pathway, Cell cycle, 2569 6537 cycle 16 homolog (S.cerevisiae) Cell division, Mitosis, Repeat, TPR repeat, Alternativesplicing NM_003904 ZNF259 zinc finger protein Nuclear protein,Zinc-finger 2570 6538 259 NM_003905 APPBP1 amyloid beta Hypotheticalprotein 2571 6539 precursor protein binding protein 1, 59 kDa NM_003909CPNE3 copine III Repeat, Phosphorylation, 2572 6540 Transferase,Serine/threonine- protein kinase NM_003915 CPNE1 copine I Repeat 25736541 NM_003923 FOXH1 forkhead box H1 Transcription regulation,Activator, 2574 6542 DNA-binding, Nuclear protein, PolymorphismNM_003931 WASF1 WAS protein family, Actin-binding 2575 6543 member 1NM_003938 AP3D1 adaptor-related Golgi stack, Protein transport, 25766544 protein complex 3, Transport, Alternative splicing, delta 1 subunitPolymorphism NM_003940 USP13 ubiquitin specific Ubl conjugation pathway,Hydrolase, 2577 6545 protease 13 Thiol protease, Multigene family,(isopeptidase T-3) Repeat, Hypothetical protein NM_003943 GENX-genethonin 1 2578 6546 3414 NM_003945 ATP6V0E ATPase, H+ Hydrolase,Hydrogen ion transport, 2579 6547 transporting, Transmembrane lysosomal9 kDa, V0 subunit e NM_003951 SLC25A14 solute carrier familyMitochondrion, Repeat, 2580 6548 25 (mitochondrial Transmembrane,Transport, carrier, brain), Alternative splicing member 14 NM_003953MPZL1 myelin protein zero- Hypothetical protein 2581 6549 like 1NM_003954 MAP3K14 mitogen-activated Hypothetical protein, Transferase,2582 6550 protein kinase Serine/threonine-protein kinase, kinase kinase14 ATP-binding, Phosphorylation NM_003967 PNR putative G-protein coupledreceptor, 2583 6551 neurotransmitter Receptor, Transmembrane receptorNM_003975 SH2D2A SH2 domain protein Angiogenesis, Phosphorylation, SH22584 6552 2A domain, SH3-binding, Alternative splicing NM_003977 AIParyl hydrocarbon Repeat, TPR repeat 2585 6553 receptor interactingprotein NM_003978 PSTPIP1 proline-serine- SH3 domain 2586 6554 threoninephosphatase interacting protein 1 NM_003983 SLC7A6 solute carrier familyHypothetical protein 2587 6555 7 (cationic amino acid transporter, y+system), member 6 NM_004031 IRF7 interferon regulatory Transcriptionregulation, DNA- 2588 6556 factor 7 binding, Nuclear protein, Activator,Alternative splicing, Collagen NM_004033 ANXA6 annexin A6 Annexin,Calcium/phospholipid- 2589 6557 binding, Repeat, Acetylation,Phosphorylation, 3D-structure NM_004037 AMPD2 adenosine Hydrolase,Nucleotide metabolism, 2590 6558 monophosphate Multigene family,Alternative splicing deaminase 2 (isoform L) NM_004039 ANXA2 annexin A2Annexin, Calcium, Calcium-binding, 2591 6559Calcium/phospholipid-binding, Repeat, Phosphorylation, Acetylation,Polymorphism NM_004044 ATIC 5-aminoimidazole-4- Purine biosynthesis,Transferase, 2592 6560 carboxamide Hydrolase, Multifunctional enzymeribonucleotide formyltransferase/IMP cyclohydrolase NM_004046 ATP5A1 ATPsynthase, H+ ATP synthesis, ATP-binding, CF(1), 2593 6561 transporting,Hydrogen ion transport, Hydrolase, mitochondrial F1 Ion transport,Transport, complex, alpha Mitochondrion, Transit peptide, subunit,isoform 1, Pyrrolidone carboxylic acid, cardiac muscle Hypotheticalprotein NM_004047 ATP6V0B ATPase, H+ Hydrolase, Hydrogen ion transport,2594 6562 transporting, ATP synthesis, Transmembrane lysosomal 21 kDa,V0 subunit c″ NM_004049 BCL2A1 BCL2-related protein Apoptosis 2595 6563A1 NM_004053 BYSL bystin-like Cell adhesion 2596 6564 NM_004054 C3AR1complement G-protein coupled receptor, 2597 6565 component 3aTransmembrane, Glycoprotein, receptor 1 Chemotaxis NM_004060 CCNG1cyclin G1 Cyclin, Cell cycle, Cell division, 2598 6566 Mitosis, Nuclearprotein NM_004070 CLCNKA chloride channel Ka Ionic channel, Iontransport, Chloride 2599 6567 channel, Chloride, Voltage-gated channel,Transmembrane, CBS domain, Repeat NM_004073 CNK cytokine-inducibleTransferase, Serine/threonine- 2600 6568 kinase protein kinase,ATP-binding, Repeat, Phosphorylation, Hypothetical protein, KinaseNM_004079 CTSS cathepsin S Hydrolase, Thiol protease, 2601 6569Lysosome, Zymogen, Signal, 3D- structure NM_004084 DEFA1 defensin, alpha1, Defensin, Antibiotic, Antiviral, 2602 6570 myeloid-related Fungicide,Signal, 3D-structure sequence NM_004090 DUSP3 dual specificityHydrolase, 3D-structure, 2603 6571 phosphatase 3 Hypothetical protein(vaccinia virus phosphatase VH1- related) NM_004092 ECHS1 enoyl CoenzymeA Fatty acid metabolism, Lyase, 2604 6572 hydratase, shortMitochondrion, Transit peptide chain, 1, mitochondrial NM_004094 EIF2S1eukaryotic Initiation factor, Protein biosynthesis, 2605 6573translation initiation Translation regulation, RNA-binding, factor 2,subunit 1 Phosphorylation, 3D-structure alpha, 35 kDa NM_004099 STOMstomatin Erythrocyte, Transmembrane, 2606 6574 Phosphorylation,Lipoprotein, Palmitate, Hypothetical protein, Transducer, Prenylation,Multigene family NM_004105 EFEMP1 EGF-containing Repeat, EGF-likedomain, Calcium- 2607 6575 fibulin-like binding, Glycoprotein, Signal,extracellular matrix Disease mutation, Polymorphism, protein 1Alternative splicing NM_004106 FCER1G Fc fragment of IgE, IgE-bindingprotein, Receptor, 2608 6576 high affinity I, Transmembrane, Signalreceptor for; gamma polypeptide NM_004107 FCGRT Fc fragment of IgG,IgG-binding protein, Receptor, 2609 6577 receptor, transporter,Transmembrane, Glycoprotein, alpha Signal, Immunoglobulin domain, 3D-structure NM_004108 FCN2 ficolin Lectin, Collagen, Repeat, 2610 6578(collagen/fibrinogen Glycoprotein, Signal, Multigene domain containingfamily lectin) 2 (hucolin) NM_004109 FDX1 ferredoxin 1 Metal-binding,Iron-sulfur, Iron, 2Fe—2S, 2611 6579 Electron transport, Mitochondrion,Transit peptide NM_004115 FGF14 fibroblast growth Growth factor 26126580 factor 14 NM_004119 FLT3 fms-related tyrosine Signal, Transferase,Tyrosine- 2613 6581 kinase 3 protein kinase, Receptor, Transmembrane,Glycoprotein, Phosphorylation, ATP-binding, Immunoglobulin domainNM_004122 GHSR growth hormone G-protein coupled receptor, 2614 6582secretagogue Transmembrane, Glycoprotein, receptor Alternative splicingNM_004126 GNG11 guanine nucleotide Transducer, Prenylation, Lipoprotein,2615 6583 binding protein (G Multigene family protein), gamma 11NM_004128 GTF2F2 general transcription Transcription regulation, DNA-2616 6584 factor IIF, binding, Helicase, ATP-binding, polypeptide 2,Nuclear protein, 3D-structure 30 kDa NM_004130 GYG glycogeninTransferase, Glycogen biosynthesis, 2617 6585 Acetylation,Phosphorylation, Glycoprotein, Alternative splicing, Hypotheticalprotein NM_004131 GZMB granzyme B Hydrolase, Serine protease, 2618 6586(granzyme 2, Zymogen, Signal, T-cell, Cytolysis, cytotoxic T- Apoptosis,Glycoprotein, 3D- lymphocyte- structure, Protease associated serineesterase 1) NM_004134 HSPA9B heat shock 70 kDa ATP-binding, Heat shock,2619 6587 protein 9B (mortalin- Chaperone, Mitochondrion, Transit 2)peptide NM_004147 DRG1 developmentally GTP-binding, Hypothetical protein2620 6588 regulated GTP binding protein 1 NM_004148 NINJ1 ninjurin 1Cell adhesion, Transmembrane, 2621 6589 Hypothetical protein NM_004152OAZ1 ornithine 2622 6590 decarboxylase antizyme 1 NM_004168 SDHAsuccinate Tricarboxylic acid cycle, 2623 6591 dehydrogenaseFlavoprotein, FAD, Oxidoreductase, complex, subunit A, Electrontransport, Mitochondrion, flavoprotein (Fp) Transit peptide, Diseasemutation, Leigh syndrome NM_004177 STX3A syntaxin 3A Neurotransmittertransport, Coiled 2624 6592 coil, Transmembrane, Alternative splicingNM_004178 TARBP2 TAR (HIV) RNA Hypothetical protein, RNA-binding, 26256593 binding protein 2 Repeat, Nuclear protein NM_004180 TANK TRAFfamily Zinc-finger, Metal-binding, 2626 6594 member-associatedAlternative splicing, 3D-structure NFKB activator NM_004183 VMD2vitelliform macular Transport, Ion transport, Ionic 2627 6595 dystrophy(Best channel, Chloride channel, Chloride, disease, bestrophin) Calcium,Alternative splicing, Disease mutation, Polymorphism, Vision,Transmembrane, Phosphorylation, Iron storage, Metal- binding,3D-structure NM_004207 SLC16A3 solute carrier family Transport, Symport,2628 6596 16 (monocarboxylic Transmembrane, Multigene family acidtransporters), member 3 NM_004221 NK4 natural killer cell Signal 26296597 transcript 4 NM_004225 MFHAS1 malignant fibrous GTP-binding 26306598 histiocytoma amplified sequence 1 NM_004235 KLF4 Kruppel-likefactor 4 Transcription regulation, Activator, 2631 6599 (gut)Zinc-finger, Metal-binding, DNA- binding, Nuclear protein, RepeatNM_004239 TRIP11 thyroid hormone Hypothetical protein, Antigen, Golgi2632 6600 receptor interactor stack, Coiled coil, Chromosomal 11translocation NM_004244 CD163 CD163 antigen Signal, Antigen 2633 6601NM_004245 TGM5 transglutaminase 5 Transferase, Acyltransferase, 26346602 Calcium-binding, Polymorphism, Alternative splicing NM_004252SLC9A3R1 solute carrier family 2635 6603 9 (sodium/hydrogen exchanger),isoform 3 regulatory factor 1 NM_004255 COX5A cytochrome cOxidoreductase, Heme, 2636 6604 oxidase subunit Va Mitochondrion, Innermembrane, Transit peptide NM_004258 IGSF2 immunoglobulin 2637 6605superfamily, member 2 NM_004263 SEMA4F sema domain, Signal,Transmembrane, 2638 6606 immunoglobulin Immunoglobulin domain, Multigenedomain (Ig), family, Neurogenesis, transmembrane Developmental protein,domain (TM) and Glycoprotein, Alternative splicing short cytoplasmicdomain, (semaphorin) 4F NM_004265 FADS2 fatty acid desaturase 2Hypothetical protein, Heme 2639 6607 NM_004272 HOMER1 homer homolog 1Coiled coil, Alternative splicing 2640 6608 (Drosophila) NM_004279 PMPCBpeptidase Chaperone, Nuclear protein, 2641 6609 (mitochondrialPhosphorylation, Hydrolase, processing) beta Metalloprotease, Zinc,Mitochondrion, Transit peptide, Hypothetical protein NM_004295 TRAF4 TNFreceptor- Apoptosis, Developmental protein, 2642 6610 associated factor4 Nuclear protein, Zinc-finger, Coiled coil, Repeat, Alternativesplicing NM_004300 ACP1 acid phosphatase 1, Hydrolase, Acetylation,Alternative 2643 6611 soluble splicing, Polymorphism, 3D-structureNM_004305 BIN1 bridging integrator 1 Alternative splicing, SH3 domain,2644 6612 Coiled coil, Endocytosis, Anti- oncogene, Differentiation,Phosphorylation, Hypothetical protein NM_004309 ARHGDIA Rho GDP GTPaseactivation, 3D-structure 2645 6613 dissociation inhibitor (GDI) alphaNM_004313 ARRB2 arrestin, beta 2 Sensory transduction, Nuclear 2646 6614protein, Alternative splicing NM_004331 BNIP3L BCL2/adenovirusApoptosis, Transmembrane, 2647 6615 E1B 19 kDa Mitochondrion interactingprotein 3- like NM_004334 BST1 bone marrow Hydrolase, NAD, Glycoprotein,GPI- 2648 6616 stromal cell antigen 1 anchor, Signal, 3D-structure,Lipoprotein, Hypothetical protein NM_004336 BUB1 BUB1 buddingTransferase, Serine/threonine- 2649 6617 uninhibited by protein kinase,ATP-binding, Cell benzimidazoles 1 cycle, Nuclear protein, Mitosis,homolog (yeast) Phosphorylation, Polymorphism NM_004337 C8orf1chromosome 8 open Meiosis 2650 6618 reading frame 1 NM_004345 CAMPcathelicidin Antibiotic, Signal, Pyrrolidone 2651 6619 antimicrobialpeptide carboxylic acid NM_004350 RUNX3 runt-related Transcriptionregulation, DNA- 2652 6620 transcription factor 3 binding, Nuclearprotein, ATP- binding, Alternative splicing NM_004358 CDC25B celldivision cycle Cell division, Mitosis, Hydrolase, 2653 6621 25BAlternative splicing, Multigene family, 3D-structure NM_004360 CDH1cadherin 1, type 1, Elongation factor, Protein 2654 6622 E-cadherinbiosynthesis, GTP-binding, (epithelial) Methylation, Multigene family,Ribosomal protein, Repeat, Hypothetical protein, Cell adhesion,Glycoprotein, Transmembrane, Calcium-binding, Signal, Phosphorylation,Disease mutation, Polymorphism, 3D-structure NM_004368 CNN2 calponin 2Calmodulin-binding, Actin-binding, 2655 6623 Multigene family, RepeatNM_004374 COX6C cytochrome c Oxidoreductase, Inner membrane, 2656 6624oxidase subunit VIc Mitochondrion NM_004375 COX11 COX11 homolog, Copper,Mitochondrion, 2657 6625 cytochrome c Transmembrane, Transit peptide,oxidase assembly Transport, Protein transport, SH3- protein (yeast)binding, Membrane, Golgi stack, Phosphorylation, Hypothetical proteinNM_004380 CREBBP CREB binding Transferase, Transcription 2658 6626protein (Rubinstein- regulation, Nuclear protein, Taybi syndrome)Activator, Bromodomain, Chromosomal translocation, Zinc- finger, Repeat,Disease mutation, 3D-structure NM_004381 CREBL1 cAMP responsiveGlycoprotein, Cell adhesion, Repeat, 2659 6627 element binding EGF-likedomain, Coiled coil, protein-like 1 Extracellular matrix, Alternativesplicing, Signal, Ehlers-Danlos syndrome, Transcription regulation,DNA-binding, Activator, Unfolded protein response, Nuclear protein,Endoplasmic reticu NM_004385 CSPG2 chondroitin sulfate Glycoprotein,Proteoglycan, Lectin, 2660 6628 proteoglycan 2 Extracellular matrix,Sushi, Signal, (versican) Repeat, EGF-like domain, Calcium,Immunoglobulin domain, Hyaluronic acid, Alternative splicing NM_004390CTSH cathepsin H Hydrolase, Protease, Thiol protease, 2661 6629Lysosome, Glycoprotein, Zymogen, Signal, 3D-structure NM_004398 DDX10DEAD (Asp-Glu-Ala- Helicase, ATP-binding, RNA-binding 2662 6630 Asp) boxpolypeptide 10 NM_004409 DMPK dystrophia Transferase, Serine/threonine-2663 6631 myotonica-protein protein kinase, ATP-binding, Coiled kinasecoil, Alternative splicing NM_004417 DUSP1 dual specificity Hydrolase,Cell cycle 2664 6632 phosphatase 1 NM_004418 DUSP2 dual specificityHydrolase, Nuclear protein, 3D- 2665 6633 phosphatase 2 structureNM_004424 E4F1 E4F transcription Metal-binding, Zinc, Zinc-finger 26666634 factor 1 NM_004427 PHC2 polyhomeotic-like 2 Hypothetical protein2667 6635 (Drosophila) NM_004446 EPRS glutamyl-prolyl-tRNAAminoacyl-tRNA synthetase, Protein 2668 6636 synthetase biosynthesis,Ligase, ATP-binding, Multifunctional enzyme, Repeat, 3D- structureNM_004450 ERH enhancer of 2669 6637 rudimentary homolog (Drosophila)NM_004453 ETFDH electron-transferring- Oxidoreductase, Electrontransport, 2670 6638 flavoprotein Flavoprotein, FAD, Iron-sulfur,4Fe—4S, dehydrogenase Mitochondrion, Transit peptide, Ubiquinone,Transmembrane, Glutaricaciduria NM_004475 FLOT2 flotillin 2 Celladhesion, Membrane 2671 6639 NM_004477 FRG1 FSHD region gene 1 Multigenefamily 2672 6640 NM_004479 FUT7 fucosyltransferase 7 Transferase,Glycosyltransferase, 2673 6641 (alpha (1,3) Transmembrane, Glycoprotein,fucosyltransferase) Signal-anchor, Golgi stack NM_004480 FUT8fucosyltransferase 8 Transferase, Glycosyltransferase, 2674 6642 (alpha(1,6) Transmembrane, Signal-anchor, fucosyltransferase) Golgi stack, SH3domain, SH3- binding, Alternative splicing NM_004482 GALNT3UDP-N-acetyl-alpha- Transferase 2675 6643 D- galactosamine:polypeptideN- acetylgalactosaminyl transferase 3 (GalNAc-T3) NM_004483 GCSH glycinecleavage Mitochondrion, Transit peptide, 2676 6644 system protein HLipoyl (aminomethyl carrier) NM_004485 GNG4 guanine nucleotideTransducer, Prenylation, Lipoprotein, 2677 6645 binding protein (GMultigene family protein), gamma 4 NM_004489 GPS2 G protein pathwayHypothetical protein 2678 6646 suppressor 2 NM_004492 GTF2A2 generaltranscription Transcription regulation, Nuclear 2679 6647 factor IIA, 2,12 kDa protein NM_004497 FOXA3 forkhead box A3 DNA-binding, Nuclearprotein, 2680 6648 Transcription regulation, Activator, PolymorphismNM_004504 HRB HIV-1 Rev binding Nuclear protein, Transport, Repeat, 26816649 protein DNA-binding, Zinc-finger NM_004506 HSF2 heat shock Heatshock, Transcription regulation, 2682 6650 transcription factor 2Nuclear protein, DNA-binding, Activator, Phosphorylation, Multigenefamily NM_004513 IL16 interleukin 16 Cytokine, Chemotaxis, Repeat, 3D-2683 6651 (lymphocyte structure chemoattractant factor) NM_004515 ILF2interleukin enhancer 2684 6652 binding factor 2, 45 kDa NM_004516 ILF3interleukin enhancer Hypothetical protein, Transcription 2685 6653binding factor 3, regulation, DNA-binding, RNA- 90 kDa binding, Nuclearprotein, Repeat, Phosphorylation, Methylation, Alternative splicingNM_004524 LLGL2 lethal giant larvae Repeat, WD repeat 2686 6654 homolog2 (Drosophila) NM_004529 MLLT3 myeloid/lymphoid or Transcriptionregulation, Activator, 2687 6655 mixed-lineage Nuclear protein,Chromosomal leukemia (trithorax translocation, Proto-oncogene homolog,Drosophila); translocated to, 3 NM_004537 NAP1L1 nucleosome Nuclearprotein 2688 6656 assembly protein 1- like 1 NM_004554 NFATC4 nuclearfactor of Hypothetical protein, Transcription 2689 6657 activatedT-cells, regulation, Activator, Nuclear cytoplasmic, protein,DNA-binding, Repeat, calcineurin- Phosphorylation dependent 4 NM_004563PCK2 phosphoenolpyruvate Gluconeogenesis, Lyase, 2690 6658 carboxykinase2 Decarboxylase, GTP-binding, (mitochondrial) Mitochondrion, Transitpeptide, Manganese NM_004566 PFKFB3 6-phosphofructo-2- Kinase,Hydrolase, Multifunctional 2691 6659 kinase/fructose-2,6- enzyme,Transferase, ATP-binding, biphosphatase 3 Phosphorylation, Multigenefamily, Alternative splicing NM_004569 PIGH phosphatidylinositolHypothetical protein, Transferase, 2692 6660 glycan, class HGlycosyltransferase NM_004573 PLCB2 phospholipase C, Hydrolase, Lipiddegradation, 2693 6661 beta 2 Transducer, Calcium NM_004578 RAB4A RAB4A,member GTP-binding, Lipoprotein, 2694 6662 RAS oncogene Prenylation,Protein transport, family Phosphorylation NM_004580 RAB27A RAB27A,member GTP-binding, Lipoprotein, 2695 6663 RAS oncogene Prenylation,Alternative splicing, family Disease mutation NM_004583 RAB5C RAB5C,member GTP-binding, Lipoprotein, 2696 6664 RAS oncogene Prenylation,Protein transport family NM_004603 STX1A syntaxin 1A (brain)Neurotransmitter transport, Coiled 2697 6665 coil, Transmembrane,Antigen, Alternative splicing, Williams-Beuren syndrome NM_004618 TOP3Atopoisomerase Isomerase, Topoisomerase, DNA- 2698 6666 (DNA) III alphabinding, Repeat, Zinc-finger, Alternative splicing, PolymorphismNM_004629 FANCG Fanconi anemia, DNA repair, Nuclear protein 2699 6667complementation group G NM_004632 DAP3 death associated Apoptosis,Ribosomal protein, 2700 6668 protein 3 Mitochondrion NM_004633 IL1R2interleukin 1 Immunoglobulin domain, Receptor, 2701 6669 receptor, typeII Glycoprotein, Transmembrane, Signal, Repeat NM_004635 MAPKAPK3mitogen-activated ATP-binding, Kinase, 2702 6670 protein kinase-Serine/threonine-protein kinase, activated protein Transferase kinase 3NM_004637 RAB7 RAB7, member RAS GTP-binding, Lipoprotein, 2703 6671oncogene family Prenylation, Protein transport, Hypothetical proteinNM_004642 CDK2AP1 CDK2-associated Anti-oncogene 2704 6672 protein 1NM_004648 PTPNS1 protein tyrosine Repeat, Signal, Transmembrane, 27056673 phosphatase, non- Immunoglobulin domain, SH3- receptor typebinding, Glycoprotein, substrate 1 Phosphorylation, Alternativesplicing, Polymorphism NM_004651 USP11 ubiquitin specific Ublconjugation pathway, Hydrolase, 2706 6674 protease 11 Thiol protease,Nuclear protein, Multigene family NM_004664 LIN7A lin-7 homolog A (C.elegans) 2707 6675 NM_004665 VNN2 vanin 2 Hydrolase, Signal,Glycoprotein, 2708 6676 GPI-anchor, Lipoprotein NM_004666 VNN1 vanin 1Hydrolase, Signal, Glycoprotein, 2709 6677 GPI-anchor, LipoproteinNM_004668 MGAM maltase- Multifunctional enzyme, 2710 6678 glucoamylaseTransmembrane, Glycoprotein, (alpha-glucosidase) Hydrolase, Glycosidase,Repeat, Signal-anchor, Sulfation NM_004682 PSIP2 PC4 and SFRS1 2711 6679interacting protein 1 NM_004689 MTA1 metastasis Zinc-finger, Nuclearprotein, 2712 6680 associated 1 Alternative splicing NM_004694 SLC16A6solute carrier family Transport, Symport, 2713 6681 16 (monocarboxylicTransmembrane, Multigene family acid transporters), member 6 NM_004706ARHGEF1 Rho guanine Guanine-nucleotide releasing factor, 2714 6682nucleotide exchange GTPase activation, Coiled coil, factor (GEF) 1Alternative splicing, Phosphorylation, 3D-structure NM_004708 PDCD5programmed cell Apoptosis 2715 6683 death 5 NM_004712 HGS hepatocytegrowth Kinase 2716 6684 factor-regulated tyrosine kinase substrateNM_004720 EDG4 endothelial G-protein coupled receptor, 2717 6685differentiation, Transmembrane, Glycoprotein, lysophosphatidic Multigenefamily, Lipoprotein, acid G-protein- Palmitate coupled receptor, 4NM_004726 REPS2 RALBP1 associated Calcium-binding, Coiled coil, 27186686 Eps domain Phosphorylation, Alternative splicing, containing 2Repeat, 3D-structure NM_004727 SLC24A1 solute carrier family Vision,Transport, Antiport, Symport, 2719 6687 24 Calcium transport,Transmembrane, (sodium/potassium/calcium Glycoprotein, Phosphorylation,exchanger), Signal, Repeat, Alternative splicing member 1 NM_004729 ALTEAc-like transposable 2720 6688 element NM_004741 NOLC1 nucleolar andcoiled- Nuclear protein, Phosphorylation, 2721 6689 body phosphoprotein1 Repeat, GTP-binding, ATP-binding, Alternative splicing NM_004748 CPR8cell cycle Hypothetical protein 2722 6690 progression 8 proteinNM_004749 CPR2 cell cycle Hypothetical protein 2723 6691 progression 2protein NM_004756 NUMBL numb homolog 2724 6692 (Drosophila)-likeNM_004757 SCYE1 small inducible Protein biosynthesis, RNA-binding, 27256693 cytokine subfamily tRNA-binding, Cytokine, 3D- E, member 1structure (endothelial monocyte-activating) NM_004762 PSCD1 pleckstrinhomology, Guanine-nucleotide releasing factor, 2726 6694 Sec7 andcoiled-coil Coiled coil, Alternative splicing, 3D- domains 1(cytohesinstructure 1) NM_004774 PPARBP PPAR binding DNA-binding, Transcription2727 6695 protein regulation, Activator, Repeat, Nuclear protein,Alternative splicing NM_004779 CNOT8 CCR4-NOT Coiled coil, Nuclearprotein, 2728 6696 transcription Alternative splicing, Hypotheticalcomplex, subunit 8 protein, Molybdenum cofactor biosynthesis, Diseasemutation, Transcription regulation, Repressor NM_004781 VAMP3vesicle-associated Synapse, Synaptosome, 2729 6697 membrane protein 3Transmembrane, Coiled coil, (cellubrevin) Multigene family NM_004786TXNL thioredoxin-like, Redox-active center, Electron 2730 6698 32 kDatransport, 3D-structure NM_004800 TM9SF2 transmembrane 9 Signal,Transmembrane 2731 6699 superfamily member 2 NM_004802 OTOF otoferlinTransmembrane, Repeat, Alternative 2732 6700 splicing, DeafnessNM_004808 NMT2 N- Transferase, Acyltransferase 2733 6701myristoyltransferase 2 NM_004814 HPRP8BP U5 snRNP-specific Repeat, WDrepeat, Hypothetical 2734 6702 40 kDa protein protein (hPrp8-binding)NM_004817 TJP2 tight junction protein Tight junction, SH3 domain,Repeat, 2735 6703 2 (zona occludens 2) Membrane, Alternative splicing,Alternative promoter usage, Nuclear protein, Phosphorylation NM_004834MAP4K4 mitogen-activated ATP-binding, Serine/threonine- 2736 6704protein kinase protein kinase, Transferase, kinase kinase kinase 4Alternative splicing NM_004848 C1orf38 chromosome 1 open Hypotheticalprotein 2737 6705 reading frame 38 NM_004854 CHST10 carbohydrateTransferase 2738 6706 sulfotransferase 10 NM_004856 KIF23anaphase-promoting Motor protein, Cell division, 2739 6707 complexsubunit 7 Microtubule, ATP-binding, Coiled coil, Mitosis, Cell cycle,Nuclear protein NM_004862 LITAF lipopolysaccharide- Hypotheticalprotein, Transcription 2740 6708 induced TNF factor regulation, Nuclearprotein NM_004868 GPSN2 glycoprotein, Transmembrane, Glycoprotein, 27416709 synaptic 2 Alternative splicing NM_004875 POLR1C polymerase (RNA) IHypothetical protein, Transferase, 2742 6710 polypeptide C, DNA-directedRNA polymerase, 30 kDa Transcription, Nuclear protein, Alternativesplicing NM_004877 GMFG glia maturation Growth factor, Ribosomal protein2743 6711 factor, gamma NM_004878 PTGES prostaglandin E Hypotheticalprotein, 2744 6712 synthase Transmembrane NM_004879 EI24 etoposideinduced 2745 6713 2.4 mRNA NM_004889 ATP5J2 ATP synthase, H+ ATPsynthesis, Hydrogen ion 2746 6714 transporting, transport, CF(0),Mitochondrion, mitochondrial F0 Acetylation, Alternative splicingcomplex, subunit f, isoform 2 NM_004900 APOBEC3B apolipoprotein BHydrolase 2747 6715 mRNA editing enzyme, catalytic polypeptide-like 3BNM_004902 RNPC2 RNA-binding region Transcription regulation, Activator,2748 6716 (RNP1, RRM) Nuclear protein, RNA-binding, containing 2 mRNAprocessing, mRNA splicing, Repeat, Alternative splicing, PolymorphismNM_004905 PRDX6 peroxiredoxin 6 Hydrolase, Oxidoreductase, 2749 6717Peroxidase, Lipid degradation, Antioxidant, Redox-active center,Multifunctional enzyme, Lysosome, 3D-structure NM_004907 ETR101immediate early ATP-binding, Coiled coil, 2750 6718 proteinMicrotubules, Motor protein NM_004910 PITPNM1 phosphatidylinositolHypothetical protein 2751 6719 transfer protein, membrane- associated 1NM_004915 ABCG1 ATP-binding ATP-binding, Transport, Hypothetical 27526720 cassette, sub-family protein, Lipid transport, G (WHITE), member 1Transmembrane, Alternative splicing, Polymorphism NM_004916 WWOX HumanOxidoreductase 2753 6721 oxidoreductase (HHCMA56) mRNA, complete cds.NM_004920 AATK apoptosis- Kinase, Hypothetical protein, ATP- 2754 6722associated tyrosine binding, Transferase kinase NM_004924 ACTN4 actinin,alpha 4 Actin-binding, Calcium-binding, 2755 6723 Repeat, Multigenefamily, Disease mutation, Nuclear protein, Hypothetical proteinNM_004928 C21orf2 chromosome 21 Alternative splicing, Polymorphism 27566724 open reading frame 2 NM_004930 CAPZB capping protein Cytoskeleton,Actin-binding, 2757 6725 (actin filament) Alternative splicing, Actincapping muscle Z-line, beta NM_004939 DDX1 DEAD (Asp-Glu-Ala- Hydrolase,ATP-binding, Helicase, 2758 6726 Asp) box polypeptide 1 RNA-bindingNM_004945 DNM2 dynamin 2 Hydrolase, Motor protein, GTP- 2759 6727binding, Microtubule, Multigene family, Endocytosis, Alternativesplicing, Hypothetical protein NM_004954 MARK2 MAP/microtubuleATP-binding, Kinase, 2760 6728 affinity-regulatingSerine/threonine-protein kinase, kinase 2 Transferase NM_004974 KCNA2potassium voltage- Transport, Ion transport, Ionic 2761 6729 gatedchannel, channel, Voltage-gated channel, shaker-related Potassiumchannel, Potassium subfamily, member 2 transport, Potassium,Transmembrane, Glycoprotein, Phosphorylation, Multigene family NM_004979KCND1 potassium voltage- Transport, Ion transport, Ionic 2762 6730 gatedchannel, Shal- channel, Voltage-gated channel, related subfamily,Potassium channel, Potassium member 1 transport, Potassium,Transmembrane, Multigene family NM_004994 MMP9 matrix Hydrolase,Metalloprotease, 2763 6731 metalloproteinase 9 Glycoprotein, Zinc,Zymogen, (gelatinase B, 92 kDa Calcium, Collagen degradation,gelatinase, 92 kDa Extracellular matrix, Repeat, Signal, type IVcollagenase) Polymorphism, 3D-structure NM_005000 NDUFA5 NADHHypothetical protein, 2764 6732 dehydrogenase Oxidoreductase, NAD,Ubiquinone, (ubiquinone) 1 alpha Mitochondrion, Acetylation subcomplex,5, 13 kDa NM_005003 NDUFAB1 NADH Fatty acid biosynthesis, 2765 6733dehydrogenase Phosphopantetheine, Mitochondrion, (ubiquinone) 1, Transitpeptide, Oxidoreductase alpha/beta subcomplex, 1, 8 kDa NM_005009 NME4non-metastatic cells Transferase, Kinase, ATP-binding, 2766 6734 4,protein expressed Mitochondrion, Transit peptide, 3D- in structureNM_005011 NRF1 nuclear respiratory Transcription regulation, DNA- 27676735 factor 1 binding, Activator, Nuclear protein, Phosphorylation,Alternative splicing NM_005022 PFN1 profilin 1 Actin-binding,Cytoskeleton, 2768 6736 Multigene family, Acetylation, 3D- structureNM_005024 SERPINB10 serine (or cysteine) Serpin, Serine proteaseinhibitor 2769 6737 proteinase inhibitor, clade B (ovalbumin), member 10NM_005025 SERPINI1 serine (or cysteine) Serpin, Serine proteaseinhibitor, 2770 6738 proteinase inhibitor, Glycoprotein, Signal, Diseaseclade I mutation (neuroserpin), member 1 NM_005026 PIK3CDphosphoinositide-3- Kinase, Transferase, Multigene 2771 6739 kinase,catalytic, family delta polypeptide NM_005029 PITX3 paired-likeHomeobox, DNA-binding, 2772 6740 homeodomain Developmental protein,Nuclear transcription factor 3 protein, Disease mutation NM_005030 PLKpolo-like kinase Transferase, Serine/threonine- 2773 6741 (Drosophila)protein kinase, ATP-binding, Repeat, Nuclear protein, PhosphorylationNM_005040 PRCP prolylcarboxypeptidase Hydrolase, Carboxypeptidase, 27746742 (angiotensinase Glycoprotein, Zymogen, Signal, C) LysosomeNM_005044 PRKX protein kinase, X- ATP-binding, Kinase, 2775 6743 linkedSerine/threonine-protein kinase, Transferase, Tyrosine-protein kinase,cAMP NM_005055 RAPSN receptor-associated Synapse, Postsynaptic membrane,2776 6744 protein of the Cytoskeleton, Phosphorylation, synapse, 43 kDMyristate, Zinc-finger, Repeat, TPR repeat, Alternative splicing,Lipoprotein, Metal-binding, Receptor NM_005056 RBBP2 retinoblastomaTrans-acting factor, Nuclear protein, 2777 6745 binding protein 2Repeat, Zinc-finger NM_005061 RPL3L ribosomal protein Ribosomal protein2778 6746 L3-like NM_005066 SFPQ splicing factor Nuclear protein,RNA-binding, DNA- 2779 6747 proline/glutamine binding, mRNA splicing,Repeat, rich (polypyrimidine Alternative splicing tract binding proteinassociated) NM_005084 PLA2G7 phospholipase A2, Hydrolase, Lipiddegradation, 2780 6748 group VII (platelet- Glycoprotein, Signal,Polymorphism, activating factor Disease mutation acetylhydrolase,plasma) NM_005085 NUP214 nucleoporin 214 kDa Hypothetical protein,Repeat, WD 2781 6749 repeat, Nuclear protein, Transport, Proto-oncogene,Chromosomal translocation, Glycoprotein NM_005091 PGLYRP peptidoglycanAntibiotic, Immune response, Signal 2782 6750 recognition proteinNM_005096 ZNF261 zinc finger protein Hypothetical protein, Chromosomal2783 6751 261 translocation, Transmembrane, Alternative splicingNM_005099 ADAMTS4 a disintegrin-like and Hydrolase, Metalloprotease,Zinc, 2784 6752 metalloprotease Signal, Glycoprotein, Zymogen,(reprolysin type) with Extracellular matrix, Hypothetical thrombospondintype protein 1 motif, 4 NM_005106 DLEC1 deleted in lung and Hypotheticalprotein 2785 6753 esophageal cancer 1 NM_005111 CRYZL1 crystallin, zetaOxidoreductase, NADP, Alternative 2786 6754 (quinone reductase)-splicing like 1 NM_005112 WDR1 WD repeat domain 1 Repeat, WD repeat,Hypothetical 2787 6755 protein, Actin-binding, Cytoskeleton, Alternativesplicing, Polymorphism NM_005134 PPP4R1 protein phosphatase Hypotheticalprotein 2788 6756 4, regulatory subunit 1 NM_005137 DGCR2 DiGeorgesyndrome Cell adhesion, Receptor, Signal, 2789 6757 critical region gene2 Transmembrane, Lectin, Glycoprotein NM_005139 ANXA3 annexin A3Annexin, Calcium/phospholipid- 2790 6758 binding, Repeat, PhospholipaseA2 inhibitor, 3D-structure, Polymorphism NM_005143 HP haptoglobinGlycoprotein, Serine protease 2791 6759 homolog, Sushi, Hemoglobin-binding, Signal, Repeat, Polymorphism NM_005148 UNC119 unc-119 homolog(C. elegans) Vision, Alternative splicing 2792 6760 NM_005151 USP14ubiquitin specific Ubl conjugation pathway, Hydrolase, 2793 6761protease 14 (tRNA- Thiol protease, Multigene family guaninetransglycosylase) NM_005165 ALDOC aldolase C, fructose- Lyase, Schiffbase, Glycolysis, 2794 6762 bisphosphate Multigene family NM_005167 ARHChypothetical protein DNA condensation, Mitosis, Cell 2795 6763 MGC19531cycle, ATP-binding, Coiled coil, Nuclear protein, Alternative splicing,Hypothetical protein, Proto- oncogene, GTP-binding, Prenylation,Lipoprotein NM_005173 ATP2A3 ATPase, Ca++ Hydrolase, Calcium transport,2796 6764 transporting, Transmembrane, Phosphorylation, ubiquitousATP-binding, Metal-binding, Magnesium, Calcium-binding, Multigenefamily, Alternative splicing NM_005174 ATP5C1 ATP synthase, H+ ATPsynthesis, CF(1), Hydrogen ion 2797 6765 transporting, transport,Hydrolase, Mitochondrion, mitochondrial F1 Transit peptide, Alternativesplicing, complex, gamma Hypothetical protein polypeptide 1 NM_005180BMI1 B lymphoma Mo- Chromatin regulator, Nuclear 2798 6766 MLV insertionregion protein, Transcription regulation, (mouse) Repressor,Zinc-finger, Proto- oncogene NM_005185 CALML3 calmodulin-like 3Calcium-binding, Repeat, 2799 6767 Methylation, 3D-structure NM_005190CCNC cyclin C Cyclin, Cell cycle, Cell division, 2800 6768 Nuclearprotein, Transcription regulation NM_005195 CEBPD KIAA0146 proteinTranscription regulation, Activator, 2801 6769 DNA-binding, Nuclearprotein NM_005197 CHES1 checkpoint Transcription regulation, Activator,2802 6770 suppressor 1 DNA-binding, Nuclear protein, Alternativesplicing NM_005199 CHRNG cholinergic receptor, Receptor, Postsynapticmembrane, 2803 6771 nicotinic, gamma Ionic channel, Glycoprotein,Signal, polypeptide Transmembrane NM_005213 CSTA cystatin A (stefin A)Thiol protease inhibitor, 3D-structure 2804 6772 NM_005217 DEFA3defensin, alpha 3, Defensin, Antibiotic, Antiviral, 2805 6773neutrophil-specific Fungicide, Signal, 3D-structure NM_005224 DRIL1 deadringer-like 1 Transcription regulation, Activator, 2806 6774(Drosophila) DNA-binding, Nuclear protein NM_005231 EMS1 ems1 sequencePhosphorylation, Repeat, SH3 2807 6775 (mammary tumor domain,Cytoskeleton and squamous cell carcinoma- associated (p80/85 srcsubstrate) NM_005239 ETS2 v-ets Proto-oncogene, DNA-binding, 2808 6776erythroblastosis Nuclear protein virus E26 oncogene homolog 2 (avian)NM_005248 FGR Gardner-Rasheed Transferase, Tyrosine-protein 2809 6777feline sarcoma viral kinase, Proto-oncogene, ATP- (v-fgr) oncogenebinding, Phosphorylation, SH2 homolog domain, SH3 domain NM_005252 FOSv-fos FBJ murine Proto-oncogene, Nuclear protein, 2810 6778 osteosarcomaviral Phosphorylation, DNA-binding, 3D- oncogene homolog structureNM_005253 FOSL2 FOS-like antigen 2 Nuclear protein, DNA-binding 28116779 NM_005255 GAK cyclin G associated Transferase, Serine/threonine-2812 6780 kinase protein kinase, ATP-binding, Nuclear protein,Endoplasmic reticulum, Cell cycle NM_005256 GAS2 growth arrest- Growtharrest, Phosphorylation, 2813 6781 specific 2 Apoptosis, Cell cycle,Cytoskeleton NM_005263 GFI1 growth factor Transcription regulation,Zinc-finger, 2814 6782 independent 1 DNA-binding, Nuclear protein,Metal- binding, Repeat, Disease mutation NM_005270 GLI2 GLI-Kruppelfamily Transcription regulation, Zinc-finger, 2815 6783 member GLI2Metal-binding, DNA-binding, Nuclear protein, Repeat, Alternativesplicing NM_005271 GLUD1 glutamate Oxidoreductase, NADP, 2816 6784dehydrogenase 1 Mitochondrion, Transit peptide, Polymorphism, Diseasemutation, Multigene family, 3D-structure NM_005273 GNB2 guaninenucleotide Transducer, Repeat, WD repeat, 2817 6785 binding protein (GMultigene family protein), beta polypeptide 2 NM_005274 GNG5 guaninenucleotide Transducer, Prenylation, Lipoprotein, 2818 6786 bindingprotein (G Multigene family protein), gamma 5 NM_005286 GPR8 Gprotein-coupled Transcription regulation, Zinc-finger, 2819 6787receptor 8 DNA-binding, Nuclear protein, Repeat, G-protein coupledreceptor, Transmembrane, Glycoprotein, Lipoprotein, Palmitate,Phosphorylation, Polymorphism NM_005291 GPR17 G protein-coupledG-protein coupled receptor, 2820 6788 receptor 17 Transmembrane,Glycoprotein, Alternative splicing, Receptor NM_005327 HADHSCL-3-hydroxyacyl- Fatty acid metabolism, 2821 6789 Coenzyme AOxidoreductase, NAD, dehydrogenase, Mitochondrion, Transit peptide, 3D-short chain structure NM_005335 HCLS1 hematopoietic cell- Repeat, SH3domain, 2822 6790 specific Lyn Phosphorylation substrate 1 NM_005340HINT1 histidine triad Hydrolase, Acetylation, 3D-structure 2823 6791nucleotide binding protein 1 NM_005345 HSPA1A heat shock 70 kDaATP-binding, Chaperone, Heat 2824 6792 protein 1A shock, Multigenefamily, 3D- structure NM_005346 HSPA1B heat shock 70 kDa ATP-binding,Chaperone, Heat 2825 6793 protein 1B shock, Multigene family, 3D-structure NM_005357 LIPE lipase, hormone- Hydrolase, Lipid degradation,2826 6794 sensitive Phosphorylation NM_005358 LMO7 LIM domain only 7 LIMdomain, Metal-binding, Zinc, 2827 6795 Hypothetical protein, Zinc-fingerNM_005360 MAF v-maf Proto-oncogene, Transcription 2828 6796musculoaponeurotic regulation, DNA-binding, Nuclear fibrosarcomaprotein, Alternative splicing, oncogene homolog Chromosomaltranslocation (avian) NM_005379 MYO1A myosin IA Myosin, Actin-binding,ATP-binding, 2829 6797 Calmodulin-binding, Repeat, Multigene family,Polymorphism, Disease mutation, Deafness NM_005381 NCL nucleolinHypothetical protein 2830 6798 NM_005402 RALA v-ral simian GTP-binding,Prenylation, 2831 6799 leukemia viral Lipoprotein oncogene homolog A(ras related) NM_005428 VAV1 vav 1 oncogene Hypothetical protein, SH3domain, 2832 6800 Proto-oncogene, Phorbol-ester binding, Zinc, SH2domain, Guanine- nucleotide releasing factor, Repeat, PhosphorylationNM_005433 YES1 v-yes-1 Yamaguchi Proto-oncogene, Tyrosine-protein 28336801 sarcoma viral kinase, Phosphorylation, oncogene homolog 1Transferase, ATP-binding, Myristate, SH3 domain, SH2 domain, LipoproteinNM_005436 D10S170 DNA segment on Proto-oncogene, Chromosomal 2834 6802chromosome 10 translocation, SH3-binding, Repeat (unique) 170 NM_005439MLF2 myeloid leukemia Nuclear protein 2835 6803 factor 2 NM_005441CHAF1B chromatin assembly DNA replication, DNA repair, Cell 2836 6804factor 1, subunit B cycle, Nuclear protein, (p60) Phosphorylation,Repeat, WD repeat NM_005451 ENIGMA enigma (LIM domain LIM domain,Metal-binding, Zinc 2837 6805 protein) NM_005463 HNRPDL heterogeneousNucleocapsid, Ribonucleoprotein 2838 6806 nuclear ribonucleoprotein D-like NM_005466 MED6 mediator of RNA Transcription regulation, Activator,2839 6807 polymerase II Receptor, Nuclear protein transcription, subunit6 homolog (yeast) NM_005472 KCNE3 potassium voltage- Transport, Iontransport, Ionic 2840 6808 gated channel, lsk- channel, Voltage-gatedchannel, related family, Potassium channel, Potassium, member 3Potassium transport, Transmembrane, Glycoprotein, Disease mutationNM_005479 FRAT1 frequently Wnt signaling pathway, Proto- 2841 6809rearranged in oncogene, 3D-structure advanced T-cell lymphomas NM_005480TROAP trophinin associated Cell adhesion, Repeat, Cytoskeleton 2842 6810protein (tastin) NM_005488 TOM1 target of myb1 Hypothetical protein,Transport, 2843 6811 (chicken) Protein transport, Membrane, 3D-structure NM_005490 SH2D3A SH2 domain Hypothetical protein 2844 6812containing 3A NM_005498 AP1M2 adaptor-related Golgi stack, Proteintransport, 2845 6813 protein complex 1, Transport, Coated pits,Endocytosis, mu 2 subunit Phosphorylation, Alternative splicingNM_005499 UBA2 SUMO-1 activating Cyclin, Hypothetical protein 2846 6814enzyme subunit 2 NM_005501 ITGA3 integrin, alpha 3 Integrin, Celladhesion, Receptor, 2847 6815 (antigen CD49C, Glycoprotein,Transmembrane, alpha 3 subunit of Signal, Phosphorylation, Repeat, VLA-3receptor) Alternative splicing, Calcium NM_005504 BCAT1 branched chainTransferase, Aminotransferase, 2848 6816 aminotransferase 1,Branched-chain amino acid cytosolic biosynthesis, Pyridoxal phosphate,Hypothetical protein NM_005505 SCARB1 scavenger receptor Transcriptionregulation, Nuclear 2849 6817 class B, member 1 protein, Receptor,Transmembrane, Glycoprotein, Polymorphism, Alternative splicingNM_005507 CFL1 cofilin 1 (non- Nuclear protein, Actin-binding, 2850 6818muscle) Cytoskeleton, Phosphorylation NM_005510 DOM3Z dom-3 homolog ZTransferase, Serine/threonine- 2851 6819 (C. elegans) protein kinase,ATP-binding, Manganese, Nuclear protein, Alternative splicing NM_005512GARP glycoprotein A Glycoprotein, Leucine-rich repeat, 2852 6820repetitions Repeat, Transmembrane, Signal predominant NM_005514 HLA-Bmajor Glycoprotein, MHC I, Signal, 2853 6821 histocompatibilityTransmembrane, Polymorphism, 3D- complex, class I, B structure,Alternative splicing, Hypothetical protein, Sulfation NM_005516 HLA-Emajor Glycoprotein, Transmembrane, 2854 6822 histocompatibilityHypothetical protein, MHC I, Signal, complex, class I, E Polymorphism,3D-structure NM_005517 HMGN2 high-mobility group Hypothetical protein,Microtubule, 2855 6823 nucleosomal binding GTP-binding, Multigenefamily, domain 2 Nuclear protein, DNA-binding, Polymorphism NM_005527HSPA1L heat shock 70 kDa ATP-binding, Multigene family, 2856 6824protein 1-like Polymorphism NM_005534 IFNGR2 interferon gamma Receptor,Transmembrane, 2857 6825 receptor 2 (interferon Glycoprotein, Signal,Repeat gamma transducer 1) NM_005541 INPP5D inositol 2858 6826polyphosphate-5- phosphatase, 145 kDa NM_005548 KARS lysyl-tRNAAminoacyl-tRNA synthetase, Protein 2859 6827 synthetase biosynthesis,Ligase, ATP-binding, Polymorphism NM_005564 LCN2 lipocalin 2Glycoprotein, Lipocalin, Signal, 3D- 2860 6828 (oncogene 24p3)structure, Pyrrolidone carboxylic acid NM_005565 LCP2 lymphocytecytosolic SH2 domain, Phosphorylation 2861 6829 protein 2 (SH2 domaincontaining leukocyte protein of 76 kDa) NM_005574 LMO2 LIM domain only 2Proto-oncogene, Repeat, LIM 2862 6830 (rhombotin-like 1) domain,Metal-binding, Zinc, Nuclear protein, Alternative splicing, Chromosomaltranslocation NM_005578 LPP LIM domain LIM domain, Metal-binding, Zinc2863 6831 containing preferred translocation partner in lipoma NM_005586MDFI MyoD family inhibitor Differentiation 2864 6832 NM_005590 MRE11AMRE11 meiotic DNA repair, Hydrolase, Nuclease, 2865 6833 recombination11 Endonuclease, Exonuclease, homolog A (S. cerevisiae) Nuclear protein,Manganese, Meiosis, Alternative splicing, Disease mutation,Polymorphism, Hypothetical protein NM_005598 NHLH1 nescient helix loopDNA-binding, Transcription 2866 6834 helix 1 regulation, DifferentiationNM_005601 NKG7 natural killer cell Transmembrane 2867 6835 group 7sequence NM_005605 PPP3CC protein phosphatase Hypothetical protein,Hydrolase, 2868 6836 3 (formerly 2B), Iron, Manganese, Calmodulin-catalytic subunit, binding, Metal-binding, Zinc, gamma isoform Multigenefamily (calcineurin A gamma) NM_005607 PTK2 PTK2 protein Hypotheticalprotein, ATP-binding, 2869 6837 tyrosine kinase 2 Transferase, Kinase,Tyrosine- protein kinase, Phosphorylation, Alternative splicing,3D-structure NM_005608 PTPRCAP protein tyrosine Transmembrane,Phosphorylation 2870 6838 phosphatase, receptor type, C- associatedprotein NM_005611 RBL2 retinoblastoma-like 2 ATP-binding, Kinase, 28716839 (p130) Serine/threonine-protein kinase, Transferase, Transcriptionregulation, DNA-binding, Nuclear protein, Cell cycle, Phosphorylation,Anti-oncogene NM_005620 S100A11 S100 calcium Calcium-binding 2872 6840binding protein A11 (calgizzarin) NM_005621 S100A12 S100 calciumCalcium-binding, Zinc, Metal- 2873 6841 binding protein A12 binding,Antibiotic, Fungicide, 3D- (calgranulin C) structure NM_005623 CCL8chemokine (C-C Cytokine, Chemotaxis, Signal, 2874 6842 motif) ligand 8Heparin-binding, Inflammatory response, Polymorphism, Pyrrolidonecarboxylic acid, 3D- structure NM_005625 SDCBP syndecan bindingCytoskeleton, Membrane, 2875 6843 protein (syntenin) Endoplasmicreticulum, Nuclear protein, Phosphorylation, Repeat, PolymorphismNM_005646 TARBP1 TAR (HIV) RNA 2876 6844 binding protein 1 NM_005647TBL1X transducin (beta)-like Repeat, WD repeat 2877 6845 1X-linkedNM_005654 NR2F1 nuclear receptor Receptor, Transcription regulation,2878 6846 subfamily 2, group F, DNA-binding, Nuclear protein, Zinc-member 1 finger, Activator NM_005658 TRAF1 TNF receptor- Apoptosis,Coiled coil 2879 6847 associated factor 1 NM_005687 FRSBphenylalanyl-tRNA Aminoacyl-tRNA synthetase, Protein 2880 6848synthetase beta- biosynthesis, Ligase, ATP-binding subunit NM_005690DNM1L dynamin 1-like Hypothetical protein 2881 6849 NM_005697 SCAMP2secretory carrier Transmembrane, Transport, Protein 2882 6850 membraneprotein 2 transport, Multigene family NM_005704 PTPRU protein tyrosineGlycoprotein, Hydrolase, Receptor, 2883 6851 phosphatase, Repeat,Signal, Transmembrane, receptor type, U Immunoglobulin domain NM_005710PQBP1 polyglutamine Nuclear protein 2884 6852 binding protein 1NM_005713 COL4A3BP collagen, type IV, Transferase, Kinase, 2885 6853alpha 3 Serine/threonine-protein kinase, (Goodpasture Coiled coil,Alternative splicing antigen) binding protein NM_005716 RGS19IP1regulator of G- 2886 6854 protein signalling 19 interacting protein 1NM_005717 ARPC5 actin related protein Cytoskeleton 2887 6855 2/3complex, subunit 5, 16 kDa NM_005720 ARPC1B actin related proteinHypothetical protein, Repeat, WD 2888 6856 2/3 complex, subunit repeat,Polymorphism 1B, 41 kDa NM_005724 TSPAN-3 transmembrane 4 Glycoprotein,Transmembrane 2889 6857 superfamily member 8 NM_005725 TSPAN-2 tetraspan2 Glycoprotein, Transmembrane 2890 6858 NM_005730 OS4 CTD (carboxy-Hypothetical protein, Nuclear protein 2891 6859 terminal domain, RNApolymerase II, polypeptide A) small phosphatase 2 NM_005731 ARPC2 actinrelated protein Cytoskeleton 2892 6860 2/3 complex, subunit 2, 34 kDaNM_005732 RAD50 RAD50 homolog (S. cerevisiae) 2893 6861 NM_005733 KIF20Akinesin family Motor protein, Microtubule, ATP- 2894 6862 member 20Abinding, Coiled coil, Golgi stack, Protein transport, TransportNM_005736 ACTR1A ARP1 actin-related Structural protein, Cytoskeleton,2895 6863 protein 1 homolog A, Multigene family centractin alpha (yeast)NM_005737 ARL7 ADP-ribosylation GTP-binding, Multigene family, 2896 6864factor-like 7 Nuclear protein NM_005741 ZNF263 zinc finger proteinTranscription regulation, Zinc-finger, 2897 6865 263 Metal-binding,Nuclear protein, DNA- binding, Repeat, Repressor NM_005759 ABI-2abl-interactor 2 Kinase, SH3 domain 2898 6866 NM_005761 PLXNC1 plexin C12899 6867 NM_005762 TRIM28 tripartite motif- Transcription regulation,Repressor, 2900 6868 containing 28 Nuclear protein, Zinc-finger, Repeat,3D-structure NM_005770 SERF2 small EDRK-rich Hypothetical protein 29016869 factor 2 NM_005771 RDHL dehydrogenase/reductase Oxidoreductase 29026870 (SDR family) member 9 NM_005772 PLAA RNA terminal Repeat, WDrepeat, Hypothetical 2903 6871 phosphate cyclase- protein, Nuclearprotein like 1 NM_005773 ZNF256 zinc finger protein Transcriptionregulation, DNA- 2904 6872 256 binding, Zinc-finger, Metal-binding,Nuclear protein, Repeat NM_005787 NOT56L asparagine-linked Hypotheticalprotein, Transferase, 2905 6873 glycosylation 3 Glycosyltransferase,homolog (yeast, Transmembrane, Endoplasmic alpha-1,3- reticulum, Diseasemutation mannosyltransferase) NM_005797 EVA1 epithelial V-like Celladhesion, Immunoglobulin 2906 6874 antigen 1 domain, Transmembrane,Glycoprotein, Signal NM_005803 FLOT1 flotillin 1 Membrane 2907 6875NM_005805 PSMD14 proteasome Proteasome 2908 6876 (prosome, macropain)26S subunit, non- ATPase, 14 NM_005811 GDF11 growth differentiationGrowth factor, Cytokine, 2909 6877 factor 11 Glycoprotein, SignalNM_005826 HNRPR heterogeneous Nucleocapsid, Ribonucleoprotein, 2910 6878nuclear Nuclear protein, RNA-binding, ribonucleoprotein R RepeatNM_005833 RAB9P40 Rab9 effector p40 2911 6879 NM_005834 TIMM17Btranslocase of inner Transport, Protein transport, 2912 6880mitochondrial Translocation, Mitochondrion, Inner membrane 17 membrane,Transmembrane homolog B (yeast) NM_005836 UK114 translational inhibitorNuclear protein 2913 6881 protein p14.5 NM_005845 ABCC4 ATP-bindingATP-binding, Glycoprotein, 2914 6882 cassette, sub-family Transmembrane,Transport, Repeat C (CFTR/MRP), member 4 NM_005849 IGSF6 immunoglobulinSignal, Hypothetical protein 2915 6883 superfamily, member 6 NM_005855RAMP1 receptor (calcitonin) Signal, Transmembrane, Transport, 2916 6884activity modifying Receptor protein 1 NM_005860 FSTL3 follistatin-like 3Glycoprotein, Repeat, Signal, 2917 6885 (secreted Chromosomaltranslocation, Proto- glycoprotein) oncogene NM_005862 STAG1 stromalantigen 1 Mitosis, Cell cycle, Chromosome 2918 6886 partition, Nuclearprotein, Phosphorylation NM_005863 NET1 neuroepithelial cell 2919 6887transforming gene 1 NM_005865 PRSS16 protease, serine, 16 Hydrolase,Serine protease, Signal 2920 6888 (thymus) NM_005866 SR-BP1 opioidreceptor, Hypothetical protein, Receptor 2921 6889 sigma 1 NM_005873RGS19 regulator of G- Signal transduction inhibitor, 2922 6890 proteinsignalling 19 Membrane, Lipoprotein, Palmitate, Phosphorylation,Autophagy, 3D- structure NM_005874 LILRB2 leukocyte Receptor, Repeat,Signal, 2923 6891 immunoglobulin-like Transmembrane, Immune response,receptor, subfamily Immunoglobulin domain, B (with TM and ITIMPhosphorylation, Glycoprotein, domains), member 2 Antigen, Multigenefamily, Alternative splicing, Polymorphism NM_005884 PAK4 p21(CDKN1A)-Hypothetical protein, ATP-binding, 2924 6892 activated kinase 4Transferase, Serine/threonine- protein kinase, Phosphorylation,Alternative splicing NM_005886 KATNB1 katanin p80 (WD Repeat, WD repeat2925 6893 repeat containing) subunit B 1 NM_005888 SLC25A3 solutecarrier family Mitochondrion, Inner membrane, 2926 6894 25(mitochondrial Repeat, Transit peptide, carrier; phosphateTransmembrane, Transport, carrier), member 3 Symport, Alternativesplicing, Hypothetical protein NM_005891 ACAT2 acetyl-Coenzyme AChaperone, ATP-binding, Multigene 2927 6895 acetyltransferase 2 family,Transferase (acetoacetyl Coenzyme A thiolase) NM_005892 FMNL formin-like1 Hypothetical protein 2928 6896 NM_005898 M11S1 membrane GPI-anchor2929 6897 component, chromosome 11, surface marker 1 NM_005900 MADH1MAD, mothers Transcription regulation, 2930 6898 againstPhosphorylation, Multigene family, decapentaplegic 3D-structure homolog1 (Drosophila) NM_005902 MADH3 MAD, mothers Transcription regulation,2931 6899 against Phosphorylation, Multigene family, decapentaplegic3D-structure homolog 3 (Drosophila) NM_005917 MDH1 malateOxidoreductase, Tricarboxylic acid 2932 6900 dehydrogenase 1, cycle, NADNAD (soluble) NM_005931 MICB MHC class I Glycoprotein, Transmembrane,MHC 2933 6901 polypeptide-related sequence B NM_005932 MIPEPmitochondrial Hydrolase, Metalloprotease, Zinc, 2934 6902 intermediateTransit peptide, Mitochondrion, peptidase Magnesium, Manganese, Calcium,Cobalt, Iron NM_005935 MLLT2 myeloid/lymphoid or Alternative splicing,Chromosomal 2935 6903 mixed-lineage translocation, Proto-oncogene, DNA-leukemia (trithorax binding, Bromodomain, Nuclear homolog, protein,Zinc-finger, Metal-binding, Drosophila); Transcription regulation,Repeat, translocated to, 2 Hypothetical protein,Serine/threonine-protein kinase, Transferase, ATP-binding, TranNM_005950 MT1G metallothionein 1G Metal-binding, Metal-thiolate cluster,2936 6904 Zinc, Copper, Cadmium, Acetylation NM_005952 MT1Xmetallothionein 1X Hypothetical protein, Metal-binding, 2937 6905Metal-thiolate cluster, Zinc, Copper, Cadmium, Acetylation NM_005953MT2A metallothionein 2A Metal-binding, Metal-thiolate cluster, 2938 6906Zinc, Acetylation, 3D-structure NM_005954 MT3 metallothionein 3Metal-binding, Metal-thiolate cluster, 2939 6907 (growth inhibitoryZinc, Copper, Acetylation factor (neurotrophic)) NM_005955 MTF1metal-regulatory Hypothetical protein, Metal-binding, 2940 6908transcription factor 1 Zinc, Zinc-finger NM_005965 MYLK myosin, lightImmunoglobulin domain, Kinase, 2941 6909 polypeptide kinase ATP-binding,Repeat, Serine/threonine-protein kinase, Transferase,Calmodulin-binding, Phosphorylation, Alternative initiation, Alternativesplicing NM_005969 NAP1L4 nucleosome Nuclear protein 2942 6910 assemblyprotein 1- like 4 NM_005975 PTK6 PTK6 protein Transferase,Tyrosine-protein 2943 6911 tyrosine kinase 6 kinase, ATP-binding, SH2domain, SH3 domain, Phosphorylation NM_005979 S100A13 S100 calciumCalcium-binding 2944 6912 binding protein A13 NM_005980 S100P S100calcium Calcium-binding, Placenta, 3D- 2945 6913 binding protein Pstructure NM_005988 SPRR2A small proline-rich Keratinocyte, Repeat,Multigene 2946 6914 protein 2A family NM_005990 STK10 serine/threonineKinase, Transferase, 2947 6915 kinase 10 Serine/threonine-proteinkinase, ATP-binding, Phosphorylation, Coiled coil NM_005998 CCT3chaperonin Chaperone, ATP-binding, Multigene 2948 6916 containing TCP1,family, Hypothetical protein subunit 3 (gamma) NM_006002 UCHL3 ubiquitincarboxyl- Ubl conjugation pathway, Hydrolase, 2949 6917 terminalesterase L3 Thiol protease, Multigene family, 3D- (ubiquitin structurethiolesterase) NM_006018 HM74 putative chemokine G-protein coupledreceptor, 2950 6918 receptor Transmembrane NM_006019 TCIRG1 T-cell,immune Hydrogen ion transport, 2951 6919 regulator 1, ATPase,Transmembrane, Glycoprotein, H+ transporting, Alternative splicing,Hypothetical lysosomal V0 protein protein a isoform 3 NM_006022 TSC22transforming growth Hypothetical protein, Transcription 2952 6920 factorbeta- regulation, Repressor, Nuclear stimulated protein protein TSC-22NM_006027 EXO1 exonuclease 1 Exonuclease, Hypothetical protein 2953 6921NM_006029 PNMA1 paraneoplastic Antigen, Tumor antigen, Nuclear 2954 6922antigen MA1 protein NM_006031 PCNT2 pericentrin 2 Coiled coil,Hypothetical protein 2955 6923 (kendrin) NM_006034 TP53I11 tumor proteinp53 Hypothetical protein 2956 6924 inducible protein 11 NM_006053 TCIRG1T-cell, immune Hydrogen ion transport, 2957 6925 regulator 1, ATPase,Transmembrane, Glycoprotein, H+ transporting, Alternative splicing,Hypothetical lysosomal V0 protein protein a isoform 3 NM_006054 RTN3reticulon 3 Hypothetical protein, 2958 6926 Transmembrane, Endoplasmicreticulum NM_006055 LANCL1 LanC lantibiotic Transmembrane 2959 6927synthetase component C-like 1 (bacterial) NM_006060 ZNFN1A1 zinc fingerprotein, Transcription regulation, Activator, 2960 6928 subfamily 1A, 1Zinc-finger, Metal-binding, DNA- (lkaros) binding, Nuclear protein,Repeat, Alternative splicing NM_006061 SGP28 cysteine-rich Glycoprotein,Signal, Multigene 2961 6929 secretory protein 3 family, PolymorphismNM_006069 MRVI1 murine retrovirus 2962 6930 integration site 1 homologNM_006070 TFG TRK-fused gene Hypothetical protein, Ligase, GMP 2963 6931biosynthesis, Purine biosynthesis, ATP-binding, Glutamineamidotransferase NM_006079 CITED2 Cbp/p300-interacting Transcriptionregulation, Nuclear 2964 6932 transactivator, with protein, Alternativesplicing Glu/Asp-rich carboxy-terminal domain, 2 NM_006088 TUBB2tubulin, beta, 2 Microtubule, GTP-binding, Multigene 2965 6933 family,Hypothetical protein NM_006093 PRG3 proteoglycan 3 2966 6934 NM_006097MYL9 myosin, light Myosin, Calcium-binding, Muscle 2967 6935 polypeptide9, protein, Phosphorylation, regulatory Acetylation, Multigene familyNM_006103 WFDC2 WAP four-disulfide Serine protease inhibitor, Repeat,2968 6936 core domain 2 Signal, Glycoprotein, Alternative splicingNM_006107 LUC7A acid-inducible Phosphorylation, Hypothetical 2969 6937phosphoprotein protein NM_006109 SKB1 SKB1 homolog (S. pombe)Transferase, Methyltransferase, 2970 6938 Alternative splicing NM_006111ACAA2 acetyl-Coenzyme A Acyltransferase, Transferase, Fatty 2971 6939acyltransferase 2 acid metabolism, Mitochondrion, (mitochondrial 3-Transit peptide oxoacyl-Coenzyme A thiolase) NM_006113 VAV3 vav 3oncogene SH3 domain, Phorbol-ester binding, 2972 6940 Zinc, SH2 domain,Repeat, Guanine- nucleotide releasing factor, Alternative splicingNM_006115 PRAME preferentially Antigen 2973 6941 expressed antigen inmelanoma NM_006117 PECI peroxisomal D3,D2- Isomerase, Hypotheticalprotein, 2974 6942 enoyl-CoA Peroxisome isomerase NM_006135 CAPZA1capping protein Actin-binding, Multigene family, 3D- 2975 6943 (actinfilament) structure, Actin capping muscle Z-line, alpha 1 NM_006138MS4A3 membrane-spanning Receptor, Transmembrane, 2976 6944 4-domains,Alternative splicing, Multigene family subfamily A, member 3(hematopoietic cell- specific) NM_006139 CD28 CD28 antigen (Tp44)Immunoglobulin domain, T-cell, 2977 6945 Glycoprotein, Signal,Transmembrane, Alternative splicing NM_006140 CSF2RA colony stimulatingReceptor, Transmembrane, 2978 6946 factor 2 receptor, Glycoprotein,Signal, Alternative alpha, low-affinity splicing (granulocyte-macrophage) NM_006142 SFN stratifin Multigene family 2979 6947 NM_006144GZMA granzyme A Hydrolase, Serine protease, 2980 6948 (granzyme 1,Zymogen, Signal, T-cell, Cytolysis, cytotoxic T- Apoptosis, 3D-structurelymphocyte- associated serine esterase 3) NM_006145 DNAJB1 DnaJ (Hsp40)Heat shock, Chaperone, 3D- 2981 6949 homolog, subfamily structure B,member 1 NM_006147 IRF6 interferon regulatory Transcription regulation,DNA- 2982 6950 factor 6 binding, Nuclear protein, Polymorphism, Diseasemutation NM_006148 LASP1 LIM and SH3 protein 1 LIM domain,Metal-binding, Zinc, 2983 6951 SH3 domain NM_006159 NELL2 NEL-like 2(chicken) EGF-like domain, Glycoprotein, 2984 6952 Repeat, SignalNM_006161 NEUROG1 neurogenin 1 DNA-binding, Nuclear protein, 2985 6953Transcription regulation, Activator, Neurogenesis, Developmentalprotein, Differentiation NM_006176 NRGN neurogranin (proteinCalmodulin-binding, 2986 6954 kinase C substrate, Phosphorylation,Neurone RC3) NM_006185 NUMA1 nuclear mitotic Immunoglobulin domain, 29876955 apparatus protein 1 Glycoprotein, Signal, Alternative splicing,Hypothetical protein NM_006196 PCBP1 poly(rC) binding Nuclear protein,RNA-binding, 2988 6956 protein 1 Ribonucleoprotein, DNA-binding,Phosphorylation, Repeat NM_006202 PDE4A phosphodiesterase Hydrolase,cAMP, Alternative 2989 6957 4A, cAMP-specific splicing, Multigene family(phosphodiesterase E2 dunce homolog, Drosophila) NM_006205 PDE6Hphosphodiesterase Hydrolase, cGMP, Vision 2990 6958 6H, cGMP-specific,cone, gamma NM_006214 PHYH phytanoyl-CoA Oxidoreductase, Peroxisome,2991 6959 hydroxylase Vitamin C, Iron, Transit peptide, (Refsum disease)Disease mutation, Deafness, Retinitis pigmentosa, Hydrolase, cGMP,Vision, Prenylation, Lipoprotein, Membrane, Hypothetical protein,Collagen NM_006224 PITPN phosphotidylinositol Lipid-binding, Transport2992 6960 transfer protein NM_006225 PLCD1 phospholipase C, Hydrolase,Lipid degradation, 2993 6961 delta 1 Transducer, Calcium-binding, RepeatNM_006238 PPARD peroxisome Receptor, Transcription regulation, 2994 6962proliferative Activator, DNA-binding, Nuclear activated receptor,protein, Zinc-finger, Multigene family, delta 3D-structure,Metal-binding NM_006242 PPP1R3D protein phosphatase Hydrolase, Glycogenmetabolism 2995 6963 1, regulatory subunit 3D NM_006243 PPP2R5A proteinphosphatase Phosphorylation, Multigene family 2996 6964 2, regulatorysubunit B (B56), alpha isoform NM_006244 PPP2R5B protein phosphatasePhosphorylation, Alternative splicing, 2997 6965 2, regulatory subunitMultigene family B (B56), beta isoform NM_006254 PRKCD protein kinase C,ATP-binding, Transferase, 2998 6966 delta Serine/threonine-proteinkinase, Phorbol-ester binding, Zinc, Repeat, Polymorphism,Phosphorylation, Membrane NM_006272 S100B S100 calcium Calcium-binding,Zinc, Metal- 2999 6967 binding protein, beta binding, 3D-structure(neural) NM_006284 TAF10 TAF10 RNA Transcription regulation, Nuclear3000 6968 polymerase II, TATA protein, Polymorphism box binding protein(TBP)-associated factor, 30 kDa NM_006287 TFPI tissue factor Serineprotease inhibitor, 3001 6969 pathway inhibitor Glycoprotein, Repeat,Blood (lipoprotein- coagulation, Signal, Alternative associatedsplicing, 3D-structure, Polymorphism coagulation inhibitor) NM_006289TLN1 talin 1 Hypothetical protein, Structural 3002 6970 protein,Cytoskeleton NM_006290 TNFAIP3 tumor necrosis Apoptosis, DNA-binding,Zinc-finger, 3003 6971 factor, alpha-induced Repeat, Hypotheticalprotein protein 3 NM_006291 TNFAIP2 tumor necrosis Angiogenesis 30046972 factor, alpha-induced protein 2 NM_006304 DSS1 split hand/footPolymorphism, 3D-structure 3005 6973 malformation (ectrodactyly) type 1NM_006310 NPEPPS aminopeptidase Hydrolase, Metalloprotease, 3006 6974puromycin sensitive Aminopeptidase, Zinc, Nuclear protein NM_006314 CNK1connector enhancer Hypothetical protein, Kinase 3007 6975 of KSR-like(Drosophila kinase suppressor of ras) NM_006317 BASP1 brain abundant,Membrane, Myristate, Neurone, 3008 6976 membrane attached Lipoproteinsignal protein 1 NM_006319 CDIPT CDP-diacylglycerol-- Transferase,Phospholipid 3009 6977 inositol 3- biosynthesis, Transmembrane,phosphatidyltransferase Magnesium, Manganese (phosphatidylinositolsynthase) NM_006321 ARIH2 ariadne homolog 2 Ubl conjugation pathway,Nuclear 3010 6978 (Drosophila) protein, Coiled coil, Zinc-finger, RepeatNM_006323 SEC24B SEC24 related gene Transport, Protein transport, Golgi3011 6979 family, member B (S. cerevisiae) stack, Endoplasmic reticulum,Multigene family NM_006324 CFDP1 craniofacial 3012 6980 developmentprotein 1 NM_006327 TIMM23 translocase of inner Transport, Proteintransport, 3013 6981 mitochondrial Translocation, Mitochondrion, Innermembrane 23 membrane, Outer membrane, homolog (yeast) TransmembraneNM_006342 TACC3 transforming, acidic Coiled coil 3014 6982 coiled-coilcontaining protein 3 NM_006344 HML2 C-type (calcium Lectin 3015 6983dependent, carbohydrate- recognition domain) lectin, superfamily member13 (macrophage- derived) NM_006345 C4orf1 solute carrier familyHypothetical protein 3016 6984 30 (zinc transporter), member 9 NM_006346PIBF1 progesterone- 3017 6985 induced blocking factor 1 NM_006351 TIMM44translocase of inner Mitochondrion, Inner membrane, 3018 6986mitochondrial Transport, Protein transport, membrane 44 Translocation,Transit peptide, ATP- homolog (yeast) binding, Receptor NM_006353 HMGN4high mobility group Nuclear protein, DNA-binding 3019 6987 nucleosomalbinding domain 4 NM_006355 TRIM38 tripartite motif- Zinc-finger,Polymorphism 3020 6988 containing 38 NM_006360 GA17 dendritic cellprotein Hypothetical protein 3021 6989 NM_006362 NXF1 nuclear RNA exportTransport, mRNA transport, Nuclear 3022 6990 factor 1 protein,RNA-binding, Repeat, Leucine-rich repeat, Multigene family, 3D-structureNM_006367 CAP CAP, adenylate Membrane, Multigene family 3023 6991cyclase-associated protein 1 (yeast) NM_006374 STK25 serine/threonineHypothetical protein, ATP-binding, 3024 6992 kinase 25 (STE20Transferase, Serine/threonine- homolog, yeast) protein kinase,Phosphorylation NM_006377 UNC13 unc-13 homolog B Phorbol-ester binding3025 6993 (C. elegans) NM_006383 KIP2 DNA-dependent Calcium-binding,Repeat 3026 6994 protein kinase catalytic subunit- interacting protein 2NM_006386 DDX17 DEAD (Asp-Glu-Ala- ATP-binding, RNA-binding, Helicase,3027 6995 Asp) box polypeptide Nuclear protein 17 NM_006387 CHERPcalcium homeostasis 3028 6996 endoplasmic reticulum protein NM_006389HYOU1 hypoxia up-regulated 1 ATP-binding, Chaperone, 3029 6997Endoplasmic reticulum, Signal, Glycoprotein NM_006395 GSA7 APG7autophagy 7- Hypothetical protein 3030 6998 like (S. cerevisiae)NM_006399 BATF basic leucine zipper Transcription regulation, DNA- 30316999 transcription factor, binding, Repressor, Phosphorylation, ATF-likeNuclear protein NM_006403 NEDD9 neural precursor cell Phosphorylation,SH3 domain, Cell 3032 7000 expressed, adhesion, Growth regulation,developmentally Cytoskeleton, Mitosis, Nuclear down-regulated 9 proteinNM_006404 PROCR protein C receptor, Blood coagulation, Receptor, Signal,3033 7001 endothelial (EPCR) Transmembrane, Glycoprotein, Antigen,Polymorphism, 3D-structure NM_006405 TM9SF1 transmembrane 9 Hypotheticalprotein, Plasmid, 3034 7002 superfamily member 1 Signal, Transmembrane,Glycoprotein NM_006406 PRDX4 peroxiredoxin 4 Antioxidant, Peroxidase,3035 7003 Oxidoreductase, Redox-active center NM_006421 BIG1 brefeldinA-inhibited Guanine-nucleotide releasing factor 3036 7004 guaninenucleotide- exchange protein 1 NM_006429 CCT7 chaperonin Chaperone,ATP-binding, Multigene 3037 7005 containing TCP1, family subunit 7 (eta)NM_006430 CCT4 chaperonin Chaperone, ATP-binding, Multigene 3038 7006containing TCP1, family, Hypothetical protein subunit 4 (delta)NM_006431 CCT2 chaperonin ATP-binding, Chaperone, Multigene 3039 7007containing TCP1, family subunit 2 (beta) NM_006433 GNLY granulysinAntibiotic, Fungicide, Signal, T-cell, 3040 7008 Alternative splicing,3D-structure NM_006435 IFITM2 interferon induced Interferon induction,3041 7009 transmembrane Transmembrane, Polymorphism protein 2 (1-8D)NM_006441 MTHFS 5,10- Ligase, Folate-binding, Acetylation, 3042 7010methenyltetrahydrofolate Magnesium, Hypothetical protein synthetase (5-formyltetrahydrofolate cyclo-ligase) NM_006451 PAIP1 poly(A) bindingHypothetical protein 3043 7011 protein interacting protein 1 NM_006452PAICS phosphoribosylaminoimidazole Multifunctional enzyme, Purine 30447012 carboxylase, biosynthesis, Ligase, Lyase,phosphoribosylaminoimidazole Decarboxylase succinocarboxamide synthetaseNM_006455 SC65 synaptonemal Nuclear protein, Antigen 3045 7013 complexprotein SC65 NM_006456 STHM sialyltransferase Transferase,Glycosyltransferase, 3046 7014 Glycoprotein, Transmembrane,Signal-anchor, Golgi stack NM_006461 SPAG5 sperm associated Hypotheticalprotein 3047 7015 antigen 5 NM_006465 DRIL2 dead ringer 3048 7016(Drosophila)-like 2 (bright and dead ringer) NM_006469 IVNS1ABPinfluenza virus NS1A Hypothetical protein 3049 7017 binding proteinNM_006471 MLC-B myosin regulatory Myosin, Calcium-binding, Muscle 30507018 light chain MRCL3 protein, Phosphorylation, Acetylation, Multigenefamily NM_006472 TXNIP thioredoxin 3051 7019 interacting proteinNM_006477 RRP22 RAS-related on GTP-binding, Prenylation, 3052 7020chromosome 22 Lipoprotein NM_006480 RGS14 regulator of G- Repeat, Thiolprotease inhibitor, 3053 7021 protein signalling 14 Alternativesplicing, Phosphorylation, Signal transduction inhibitor NM_006495 EVI2Becotropic viral Proto-oncogene, Transmembrane, 3054 7022 integrationsite 2B Glycoprotein, Signal NM_006542 SPHAR S-phase response 3055 7023(cyclin-related) NM_006545 NPR2L homologous to yeast Hypotheticalprotein 3056 7024 nitrogen permease (candidate tumor suppressor)NM_006560 CUGBP1 CUG triplet repeat, Hypothetical protein, mRNA 30577025 RNA binding protein 1 processing, RNA-binding, Repeat, Nuclearprotein, Alternative splicing NM_006567 FARS1 phenylalanine-tRNAAminoacyl-tRNA synthetase 3058 7026 synthetase 1 (mitochondrial)NM_006568 CGR19 cell growth regulator Metal-binding, Zinc, Zinc-finger3059 7027 with ring finger domain 1 NM_006575 MAP4K5 mitogen-activatedATP-binding, Kinase, Transferase, 3060 7028 protein kinaseTyrosine-protein kinase, kinase kinase kinase 5 Serine/threonine-proteinkinase NM_006578 GNB5 guanine nucleotide Repeat, WD repeat, Transducer,3061 7029 binding protein (G Alternative splicing, Multigene family,protein), beta 5 Hypothetical protein NM_006589 C1orf2 chromosome 1 openHypothetical protein 3062 7030 reading frame 2 NM_006598 SLC12A7 solutecarrier family Transport, Ion transport, Symport, 3063 7031 12Potassium, Potassium transport, (potassium/chloride Transmembrane,Alternative splicing transporters), member 7 NM_006636 MTHFD2 methyleneMultifunctional enzyme, One-carbon 3064 7032 tetrahydrofolatemetabolism, Oxidoreductase, NAD, dehydrogenase Hydrolase, Mitochondrion,Transit (NAD+ dependent), peptide, Magnesium methenyltetrahydrofolatecyclohydrolase NM_006638 RNASEP1 ribonuclease P1 Hydrolase, Nuclearprotein, tRNA 3065 7033 processing NM_006643 SDCCAG3 serologicallydefined Hypothetical protein 3066 7034 colon cancer antigen 3 NM_006644HSPH1 heat shock ATP-binding, Heat shock, Multigene 3067 7035 105kDa/110 kDa family, Alternative splicing protein 1 NM_006646 WASF3 WASprotein family, Actin-binding, Coiled coil 3068 7036 member 3 NM_006650CPLX2 complexin 2 Neurotransmitter transport 3069 7037 NM_006660 CLPXClpX caseinolytic Hypothetical protein, ATP-binding, 3070 7038 proteaseX homolog Chaperone, Mitochondrion, Transit (E. coli) peptide,Zinc-finger NM_006667 PGRMC1 progesterone Receptor, Steroid-binding,3071 7039 receptor membrane Transmembrane, Microsome component 1NM_006669 LILRB1 leukocyte Receptor, Repeat, Signal, 3072 7040immunoglobulin-like Transmembrane, Immune response, receptor, subfamilyImmunoglobulin domain, B (with TM and ITIM Phosphorylation,Glycoprotein, domains), member 1 Antigen, Multigene family, Alternativesplicing, Polymorphism, 3D-structure NM_006676 USP20 ubiquitin specificUbl conjugation pathway, Hydrolase, 3073 7041 protease 20 Thiolprotease, Multigene family NM_006680 ME3 malic enzyme 3, Oxidoreductase,NADP, 3074 7042 NADP(+)- Mitochondrion, Transit peptide dependent,mitochondrial NM_006681 NMU neuromedin U Neuropeptide, Cleavage on pairof 3075 7043 basic residues, Amidation, Signal NM_006682 FGL2fibrinogen-like 2 T-cell, Glycoprotein, Signal, 3076 7044 PolymorphismNM_006700 FLN29 FLN29 gene product 3077 7045 NM_006704 SUGT1 SGT1,suppressor of Ubl conjugation pathway, Repeat, 3078 7046 G2 allele ofSKP1 TPR repeat (S. cerevisiae) NM_006705 GADD45G growth arrest andDifferentiation, Apoptosis 3079 7047 DNA-damage- inducible, gammaNM_006706 TCERG1 transcription 3080 7048 elongation regulator 1 (CA150)NM_006708 GLO1 glyoxalase I Lyase, Zinc, Polymorphism, 3D- 3081 7049structure NM_006710 COP9 COP9 signalosome 3082 7050 subunit 8 NM_006719ABLIM1 actin binding LIM LIM domain, Metal-binding, Zinc, 3083 7051protein 1 Hypothetical protein NM_006721 ADK adenosine kinaseTransferase, Kinase, Purine salvage, 3084 7052 Magnesium, Alternativesplicing, 3D- structure NM_006732 FOSB FBJ murine Nuclear protein,DNA-binding 3085 7053 osteosarcoma viral oncogene homolog B NM_006747SIPA1 signal-induced GTPase activation, Coiled coil, 3086 7054proliferation- Nuclear protein, Membrane associated gene 1 NM_006748 SLASrc-like-adaptor SH2 domain, SH3 domain, 3087 7055 Myristate,Phosphorylation, Lipoprotein NM_006750 SNTB2 syntrophin, beta 2Actin-binding, Cytoskeleton, 3088 7056 (dystrophin- Microtubule,Calcium-binding, associated protein Calmodulin-binding, Membrane, A1, 59kDa, basic Phosphorylation, Repeat, component 2) Polymorphism, Multigenefamily, Alternative splicing NM_006755 TALDO1 transaldolase 1Hypothetical protein, Pentose shunt, 3089 7057 Transferase, Diseasemutation, 3D- structure NM_006756 TCEA1 transcription Transcriptionregulation, Zinc-finger, 3090 7058 elongation factor A DNA-binding,Nuclear protein, (SII), 1 Alternative splicing, 3D-structure NM_006760UPK2 uroplakin 2 Endoplasmic reticulum, Signal, 3091 7059 Transmembrane,Glycoprotein NM_006761 YWHAE tyrosine 3- Neurone, Acetylation, Multigene3092 7060 monooxygenase/tryptophan family 5- monooxygenase activationprotein, epsilon polypeptide NM_006762 LAPTM5 Lysosomal- Transmembrane,Lysosome 3093 7061 associated multispanning membrane protein-5 NM_006763BTG2 BTG family, member 2 Signal 3094 7062 NM_006770 MARCO macrophageCollagen, Transmembrane, 3095 7063 receptor with Receptor, Glycoprotein,Signal- collagenous anchor structure NM_006783 GJB6 gap junctionprotein, Gap junction, Transmembrane, 3096 7064 beta 6 (connexin 30)Deafness, Disease mutation NM_006784 WDR3 WD repeat domain 3 WD repeat,Repeat, Nuclear protein 3097 7065 NM_006787 MAGED2 melanoma antigen,Antigen, Multigene family, 3098 7066 family D, 2 Polymorphism,Alternative splicing NM_006795 EHD1 EH-domain Calcium-binding,ATP-binding, 3099 7067 containing 1 Coiled coil NM_006801 KDELR1 KDEL(Lys-Asp-Glu- Endoplasmic reticulum, 3100 7068 Leu) endoplasmicTransmembrane, Protein transport, reticulum protein Receptor,Hypothetical protein, retention receptor 1 Transport NM_006805 HNRPA0heterogeneous Nuclear protein, RNA-binding, 3101 7069 nuclearRibonucleoprotein, Repeat, ribonucleoprotein A0 Methylation NM_006806BTG3 BTG family, member 3 Alternative splicing 3102 7070 NM_006810 PDIRfor protein disulfide Isomerase, Redox-active center, 3103 7071isomerase-related Endoplasmic reticulum, Repeat, Signal NM_006812 OS-9amplified in Hypothetical protein, Signal, 3104 7072 osteosarcomaAlternative splicing, Polymorphism NM_006818 AF1Q ALL1-fused geneProto-oncogene, Chromosomal 3105 7073 from chromosome translocation 1qNM_006823 PKIA protein kinase Protein kinase inhibitor, 3D-structure3106 7074 (cAMP-dependent, catalytic) inhibitor alpha NM_006824 EBNA1BP2EBNA1 binding Ribosome biogenesis, Nuclear 3107 7075 protein 2 protein,Coiled coil NM_006825 CKAP4 cytoskeleton- Hypothetical protein 3108 7076associated protein 4 NM_006826 YWHAQ tyrosine 3- Transcriptionregulation, Repressor, 3109 7077 monooxygenase/tryptophan Activator,Nuclear protein, Zinc- 5- finger, Metal-binding, DNA-binding,monooxygenase Repeat, 3D-structure, Tight junction, activation protein,Immunoglobulin domain, theta polypeptide Glycoprotein, Transmembrane,Signal, Neurone, Phosphorylation, Multigene family NM_006827 TMP21transmembrane Transport, Protein transport, 3110 7078 traffickingprotein Transmembrane, Signal, Glycoprotein, Golgi stack, PolymorphismNM_006838 METAP2 methionyl Hydrolase, Aminopeptidase, Cobalt, 3111 7079aminopeptidase 2 3D-structure, Hypothetical protein NM_006840 LILRB5leukocyte Receptor, Repeat, Signal, 3112 7080 immunoglobulin-likeTransmembrane, Immune response, receptor, subfamily Immunoglobulindomain, B (with TM and ITIM Phosphorylation, Glycoprotein, domains),member 2 Antigen, Multigene family, Alternative splicing NM_006863LILRA1 leukocyte Immune response, Receptor, 3113 7081immunoglobulin-like Repeat, Signal, Transmembrane, receptor, subfamilyImmunoglobulin domain, B (with TM and ITIM Glycoprotein, Antigen,Alternative domains), member 1 splicing, Multigene family NM_006864LILRB3 leukocyte Receptor, Repeat, Signal, 3114 7082 immunoglobulin-likeTransmembrane, Immune response, receptor, subfamily Immunoglobulindomain, B (with TM and ITIM Phosphorylation, Glycoprotein, domains),member 3 Antigen, Multigene family, Alternative splicing, PolymorphismNM_006865 LILRA3 leukocyte Receptor, Repeat, Signal, Immune 3115 7083immunoglobulin-like response, Immunoglobulin domain, receptor, subfamilyGlycoprotein, Antigen, Multigene A (without TM family, Polymorphismdomain), member 3 NM_006866 LILRA2 leukocyte Immune response, Receptor,3116 7084 immunoglobulin-like Repeat, Signal, Transmembrane, receptor,subfamily Immunoglobulin domain, B (with TM and ITIM Glycoprotein,Antigen, Alternative domains), member 1 splicing, Polymorphism,Multigene family NM_006868 RAB31 RAB31, member GTP-binding, Lipoprotein,3117 7085 RAS oncogene Prenylation family NM_006869 CENTA1 centaurin,alpha 1 3118 7086 NM_006876 B3GNT6 UDP- Transferase,Glycosyltransferase, 3119 7087 GlcNAc:betaGal Transmembrane,Signal-anchor, beta-1,3-N- Glycoprotein, Golgi stackacetylglucosaminyltransferase 6 NM_006890 CEACAM7 carcinoembryonicImmunoglobulin domain, Antigen, 3120 7088 antigen-related cell Membrane,Signal, Glycoprotein, adhesion molecule 7 Lipoprotein, GPI-anchor,Repeat, Alternative splicing NM_006892 DNMT3B DNA (cytosine-5-)-Transferase, Methyltransferase, 3121 7089 methyltransferase 3Zinc-finger, Zinc, Metal-binding, beta Nuclear protein, Ubl conjugation,Alternative splicing, Disease mutation NM_006913 RNF5 ring fingerprotein 5 Hypothetical protein 3122 7090 NM_006923 SDF2 stromalcell-derived Signal, Repeat 3123 7091 factor 2 NM_006930 SKP1A S-phasekinase- Ubl conjugation pathway, Alternative 3124 7092 associatedprotein splicing, 3D-structure 1A (p19A) NM_006931 SLC2A3 solute carrierfamily Sugar transport, Transmembrane, 3125 7093 2 (facilitated glucoseTransport, Glycoprotein, Multigene transporter), family member 3NM_006932 SMTN smoothelin Structural protein, Alternative 3126 7094splicing NM_006936 SMT3H1 SMT3 suppressor of Ubl conjugation pathway3127 7095 mif two 3 homolog 1 (yeast) NM_006938 SNRPD1 small nuclearNuclear protein, Ribonucleoprotein, 3128 7096 ribonucleoprotein D1 mRNAsplicing, mRNA processing, polypeptide 16 kDa Systemic lupuserythematosus, Repeat, Methylation, 3D-structure NM_006941 SOX10 SRY(sex Transcription regulation, DNA- 3129 7097 determining regionbinding, Nuclear protein, Disease Y)-box 10 mutation, Hirschsprungdisease, Deafness NM_006945 SPRR2B small proline-rich Keratinocyte,Repeat, Multigene 3130 7098 protein 2B family NM_006947 SRP72 signalrecognition ATP-binding, Kinase, Transferase, 3131 7099 particle 72 kDaSignal recognition particle, Ribonucleoprotein NM_006987 RPH3ALrabphilin 3A-like Hypothetical protein 3132 7100 (without C2 domains)NM_006993 NPM3 nucleophosmin/nucleoplasmin, 3 Nuclear protein,Chaperone, 3133 7101 Phosphorylation NM_007000 UPK1A uroplakin 1AHypothetical protein, 3134 7102 Transmembrane, Glycoprotein NM_007007CPSF6 cleavage and 3135 7103 polyadenylation specific factor 6, 68 kDaNM_007008 RTN4 reticulon 4 Endoplasmic reticulum, Alternative 3136 7104splicing, Transmembrane, Hypothetical protein NM_007014 WWP2 Nedd-4-likeUbl conjugation pathway, Ligase, 3137 7105 ubiquitin-protein Repeatligase NM_007022 101F6 putative tumor 3138 7106 suppressor 101F6NM_007024 PL6 placental protein 6 Transmembrane 3139 7107 NM_007032HRIHFB2122 Tara-like protein Hypothetical protein, Cytoskeleton, 31407108 Actin-binding, Coiled coil, Nuclear protein NM_007033 RER1 RER1homolog (S. cerevisiae) Transmembrane, Golgi stack 3141 7109 NM_007034DNAJB4 DnaJ (Hsp40) Chaperone, Heat shock 3142 7110 homolog, subfamilyB, member 4 NM_007043 HRB2 HIV-1 rev binding 3143 7111 protein 2NM_007054 KIF3A kinesin family Motor protein, Microtubule, ATP- 31447112 member 3A binding, Coiled coil, Neurone NM_007056 SWAP2 splicingfactor, mRNA processing, mRNA splicing, 3145 7113 arginine/serine-richNuclear protein, Alternative splicing, 16 (suppressor-of- Polymorphismwhite-apricot homolog, Drosophila) NM_007059 KPTN kaptin (actin binding3146 7114 protein) NM_007062 PWP1 nuclear Repeat, WD repeat, Nuclearprotein, 3147 7115 phosphoprotein Phosphorylation similar to S.cerevisiae PWP1 NM_007063 TBC1D8 TBC1 domain family, GTPase activation3148 7116 member 8 (with GRAM domain) NM_007065 CDC37 CDC37 celldivision Chaperone 3149 7117 cycle 37 homolog (S. cerevisiae) NM_007070FAP48 glomulin, FKBP Coiled coil, Phosphorylation, 3150 7118 associatedprotein Alternative splicing, Disease mutation, Polymorphism NM_007074CORO1A coronin, actin Actin-binding, Repeat, WD repeat, 3151 7119binding protein, 1A Coiled coil, Polymorphism NM_007077 AP4S1adaptor-related Coated pits, Endocytosis 3152 7120 protein complex 4,sigma 1 subunit NM_007098 CLTCL1 clathrin, heavy Coated pits,Alternative splicing 3153 7121 polypeptide-like 1 NM_007099 ACP1 acidphosphatase 1, Hydrolase, Acetylation, Alternative 3154 7122 solublesplicing, Polymorphism, 3D-structure NM_007108 TCEB2 transcriptionTranscription regulation, Ubl 3155 7123 elongation factor B conjugationpathway, Nuclear (SIII), polypeptide 2 protein, 3D-structure (18 kDa,elongin B) NM_007115 TNFAIP6 tumor necrosis Cell adhesion, Signal,Glycoprotein, 3156 7124 factor, alpha-induced Polymorphism, 3D-structureprotein 6 NM_007145 ZNF146 zinc finger protein Zinc-finger, DNA-binding,Metal- 3157 7125 146 binding, Nuclear protein, Repeat NM_007152 ZNF195zinc finger protein Zinc-finger, Metal-binding, DNA- 3158 7126 195binding, Nuclear protein, Alternative splicing NM_007161 LST1 leukocytespecific Signal, Immune response, Cell 3159 7127 transcript 1 shape,Transmembrane, Alternative splicing, Receptor NM_007169 PEMTphosphatidylethanol Phospholipid biosynthesis, 3160 7128 amine N-Transferase, Methyltransferase, methyltransferase Transmembrane,Mitochondrion, Endoplasmic reticulum, Polymorphism NM_007172 NUP50nucleoporin 50 kDa Hypothetical protein, Nuclear 3161 7129 protein,Transport, Protein transport, Repeat, Porin NM_007178 UNRIPunr-interacting Hypothetical protein, Repeat, WD 3162 7130 proteinrepeat NM_007186 CEP2 centrosomal protein 2 Cell cycle, Coiled coil,3163 7131 Phosphorylation, Alternative splicing, Polymorphism NM_007205TREX2 three prime repair Hypothetical protein, Proteasome, 3164 7132exonuclease 2 Exonuclease NM_007208 MRPL3 mitochondrial Ribosomalprotein, Mitochondrion 3165 7133 ribosomal protein L3 NM_007212 RNF2ring finger protein 2 Metal-binding, Zinc, Zinc-finger 3166 7134NM_007213 JM4 JM4 protein 3167 7135 NM_007219 RNF24 ring finger protein24 Zinc-finger 3168 7136 NM_007222 ZHX1 zinc-fingers and Homeobox,Metal-binding, Nuclear 3169 7137 homeoboxes 1 protein, Zinc, Zinc-fingerNM_007238 PXMP4 peroxisomal Peroxisome, Transmembrane, 3170 7138membrane protein 4, Glycoprotein, Polymorphism 24 kDa NM_007240 DUSP12dual specificity Hydrolase, Zinc, Metal-binding 3171 7139 phosphatase 12NM_007248 TREX1 three prime repair Hypothetical protein, Exonuclease3172 7140 exonuclease 1 NM_007255 B4GALT7 xylosylprotein betaGlycosyltransferase, Transferase, 3173 7141 1,4- Glycoprotein,Transmembrane, galactosyltransferase, Signal-anchor, Golgi stack,polypeptide 7 Multigene family, Disease mutation, (galactosyltransferaseEhlers-Danlos syndrome I) NM_007274 BACH brain acyl-CoA Hydrolase,Serine esterase, Repeat, 3174 7142 hydrolase Alternative splicingNM_007278 GABARAP GABA(A) receptor- Receptor 3175 7143 associatedprotein NM_007284 PTK9L protein tyrosine Hypothetical protein, Kinase3176 7144 kinase 9-like (A6- related protein) NM_007311 BZRPbenzodiazapine Mitochondrion, Receptor, 3177 7145 receptor (peripheral)Transmembrane, Polymorphism NM_007317 KIF22 kinesin family DNA-binding,Motor protein, 3178 7146 member 22 Microtubule, ATP-binding, Coiledcoil, Nuclear protein NM_007318 PSEN1 presenilin 1 Transmembrane,Phosphorylation, 3179 7147 (Alzheimer disease Endoplasmic reticulum,Golgi stack, 3) Alzheimer's disease, Disease mutation, Polymorphism,Alternative splicing NM_007320 RANBP3 RAN binding protein 3 Hypotheticalprotein 3180 7148 NM_007334 KLRD1 killer cell lectin-like Antigen,Receptor, Glycoprotein, 3181 7149 receptor subfamily Transmembrane,Signal-anchor, D, member 1 Lectin, Alternative splicing, 3D- structureNM_007346 OGFR opioid growth factor Receptor, Growth regulation, 31827150 receptor Repeat, Alternative splicing NM_007360 D12S2489E killercell lectin-like Receptor, Transmembrane, 3183 7151 receptor subfamilyMultigene family, Signal-anchor, K, member 1 Lectin, Glycoprotein,Polymorphism, 3D-structure NM_007375 TARDBP TAR DNA binding DNA-binding,RNA-binding, Nuclear 3184 7152 protein protein, Transcriptionregulation, Repressor, mRNA processing, mRNA splicing, Repeat NM_009588LTB lymphotoxin beta Cytokine, Transmembrane, 3185 7153 (TNFsuperfamily, Glycoprotein, Signal-anchor, member 3) Alternativesplicing, Polymorphism NM_012062 DNM1L dynamin 1-like Hypotheticalprotein 3186 7154 NM_012064 MIP major intrinsic Gap junction, Transport,3187 7155 protein of lens fiber Transmembrane, Phosphorylation, Eye lensprotein NM_012079 DGAT1 diacylglycerol O- Transferase, Acyltransferase,3188 7156 acyltransferase Transmembrane, Endoplasmic homolog 1 (mouse)reticulum, Hypothetical protein NM_012084 GLUD2 glutamate Hypotheticalprotein 3189 7157 dehydrogenase 2 NM_012086 GTF3C3 general transcriptionHypothetical protein 3190 7158 factor IIIC, polypeptide 3, 102 kDaNM_012089 ABCB10 ATP-binding ATP-binding, Transmembrane, 3191 7159cassette, sub-family Transport, Mitochondrion, Inner B (MDR/TAP),membrane, Transit peptide, member 10 Polymorphism NM_012094 PRDX5peroxiredoxin 5 Antioxidant, Peroxisome, 3192 7160 Mitochondrion,Transit peptide, Alternative initiation, Polymorphism, 3D-structureNM_012100 DNPEP aspartyl Hydrolase, Aminopeptidase, 3193 7161aminopeptidase Metalloprotease, Zinc, Hypothetical protein NM_012108BRDG1 BCR downstream 3194 7162 signaling 1 NM_012114 CASP14 caspase 14,Hydrolase, Thiol protease, 3195 7163 apoptosis-related Apoptosis,Zymogen cysteine protease NM_012124 CHORDC1 cysteine and 3196 7164histidine-rich domain (CHORD)- containing, zinc binding protein 1NM_012130 CLDN14 claudin 14 Tight junction, Transmembrane, 3197 7165Polymorphism, Disease mutation, Deafness NM_012142 CCNDBP1 cyclin D-typeCyclin, Hypothetical protein 3198 7166 binding-protein 1 NM_012143TFIP11 tuftelin interacting Biomineralization, Nuclear protein, 31997167 protein 11 Alternative splicing NM_012151 F8A coagulation factorHypothetical protein 3200 7168 VIII-associated (intronic transcript)NM_012168 FBXO2 F-box only protein 2 Ubl conjugation pathway 3201 7169NM_012185 FOXE2 forkhead box E2 DNA-binding, Nuclear protein, 3202 7170Transcription regulation NM_012198 GCA grancalcin, EF-handCalcium-binding, Repeat, 3D- 3203 7171 calcium binding structure proteinNM_012203 GRHPR glyoxylate Hypothetical protein, 3204 7172reductase/hydroxypyruvate Oxidoreductase, Pyruvate reductase NM_012214MGAT4A mannosyl (alpha- Glycosyltransferase, Transferase 3205 71731,3-)-glycoprotein beta-1,4-N- acetylglucosaminyltransferase, isoenzymeA NM_012218 ILF3 interleukin enhancer Hypothetical protein,Transcription 3206 7174 binding factor 3, regulation, DNA-binding, RNA-90 kDa binding, Nuclear protein, Repeat, Phosphorylation, Methylation,Alternative splicing NM_012228 PILB pilin-like transcriptionHypothetical protein 3207 7175 factor NM_012229 NT5C2 5′-nucleotidase,Hydrolase, Allosteric enzyme 3208 7176 cytosolic II NM_012236 SCMH1 sexcomb on midleg 3209 7177 homolog 1 (Drosophila) NM_012244 SLC7A8 solutecarrier family Hypothetical protein, Transport, 3210 7178 7 (cationicamino Amino-acid transport, acid transporter, y+ Transmembrane system),member 8 NM_012250 RRAS2 related RAS viral (r- GTP-binding, Prenylation,3211 7179 ras) oncogene Lipoprotein, Proto-oncogene, homolog 2 Diseasemutation NM_012255 XRN2 5′-3′ mRNA processing, Hydrolase, 3212 7180exoribonuclease 2 Nuclease, Exonuclease, Nuclear protein, RNA-binding,Zinc-finger NM_012258 HEY1 hairy/enhancer-of- Hypothetical protein,Transcription 3213 7181 split related with regulation, DNA-binding,Nuclear YRPW motif 1 protein NM_012262 HS2ST1 heparan sulfate 2-O-Hypothetical protein, Transferase 3214 7182 sulfotransferase 1 NM_012282KCNE1L potassium voltage- Transmembrane, Glycoprotein, 3215 7183 gatedchannel, lsk- Alport syndrome, Deafness, related family, Elliptocytosismember 1-like NM_012286 MORF4L2 mortality factor 4 like 2 Growthregulation, Nuclear protein 3216 7184 NM_012290 TLK1 tousled-like kinase1 ATP-binding, Kinase, 3217 7185 Serine/threonine-protein kinase,Transferase, Chromatin regulator, Cell cycle, DNA damage, Nuclearprotein, Coiled coil, Phosphorylation, Alternative splicing NM_012295CABIN1 calcineurin binding Hypothetical protein, 3218 7186 protein 1Phosphorylation, Repeat, TPR repeat NM_012329 MMD monocyte toTransmembrane 3219 7187 macrophage differentiation- associated NM_012331MSRA methionine sulfoxide Oxidoreductase 3220 7188 reductase A NM_012341CRFG GTP binding protein 4 GTP-binding, Nuclear protein 3221 7189NM_012342 NMA putative Transmembrane, Signal, 3222 7190 transmembraneGlycoprotein protein NM_012343 NNT nicotinamide Oxidoreductase, NAD,NADP, 3223 7191 nucleotide Transmembrane, Mitochondrion,transhydrogenase Transit peptide, 3D-structure, Hypothetical proteinNM_012347 FBXO9 F-box only protein 9 Hypothetical protein, Ublconjugation 3224 7192 pathway, TPR repeat NM_012383 OSTF1 osteoclastHypothetical protein, ANK repeat, 3225 7193 stimulating factor 1 Repeat,SH3 domain NM_012384 GMEB2 glucocorticoid Trans-acting factor, Nuclearprotein, 3226 7194 modulatory element DNA-binding, Coiled coil bindingprotein 2 NM_012387 PADI4 peptidyl arginine Hydrolase, Calcium-binding,3227 7195 deiminase, type IV Multigene family NM_012390 PROL5 prolinerich 5 Saliva 3228 7196 (salivary) NM_012392 PEF PEF protein with aCalcium-binding 3229 7197 long N-terminal hydrophobic domain (peflin)NM_012400 PLA2G2D phospholipase A2, Hydrolase, Lipid degradation,Signal, 3230 7198 group IID Calcium, Polymorphism NM_012403 ANP32Cacidic (leucine-rich) 3231 7199 nuclear phosphoprotein 32 family, memberC NM_012413 QPCT glutaminyl-peptide Transferase, Acyltransferase,Signal, 3232 7200 cyclotransferase Polymorphism (glutaminyl cyclase)NM_012434 SLC17A5 solute carrier family Transmembrane, Hypothetical 32337201 17 (anion/sugar protein, Sugar transport transporter), member 5NM_012445 SPON2 spondin 2, Hypothetical protein, Matrix protein 32347202 extracellular matrix protein NM_012446 SSBP2 single-stranded DNADNA-binding, Nuclear protein 3235 7203 binding protein 2 NM_012455 TICSEC7 homolog 3236 7204 NM_012460 TIMM9 translocase of inner Transport,Protein transport, 3237 7205 mitochondrial Translocation, Mitochondrion,Inner membrane 9 membrane, Hypothetical protein homolog (yeast)NM_012463 ATP6V0A2 ATPase, H+ Hydrogen ion transport, 3238 7206transporting, Transmembrane, Glycoprotein, lysosomal V0 Hypotheticalprotein subunit a isoform 2 NM_012483 GNLY granulysin Antibiotic,Fungicide, Signal, T-cell, 3239 7207 Alternative splicing, 3D-structureNM_012484 HMMR hyaluronan- Hyaluronic acid, Alternative splicing, 32407208 mediated motility Repeat, Glycoprotein, Antigen receptor (RHAMM)NM_012485 HMMR hyaluronan- Hyaluronic acid, Alternative splicing, 32417209 mediated motility Repeat, Glycoprotein, Antigen receptor (RHAMM)NM_013229 APAF1 apoptotic protease Apoptosis, ATP-binding, Repeat, 32427210 activating factor WD repeat, Alternative splicing, 3D- structureNM_013235 RNASE3L nuclear RNase III Ribosome biogenesis, Hydrolase, 32437211 Drosha Nuclease, Endonuclease, Repeat, RNA-binding, Nuclearprotein, Alternative splicing NM_013236 E46L like mouse brainHypothetical protein 3244 7212 protein E46 NM_013242 GTL3 likelyortholog of 3245 7213 mouse gene trap locus 3 NM_013248 NXT1 NTF2-likeexport Transport, Protein transport, Nuclear 3246 7214 factor 1 protein,3D-structure NM_013252 CLECSF5 C-type (calcium Transmembrane, Lectin3247 7215 dependent, carbohydrate- recognition domain) lectin,superfamily member 5 NM_013258 ASC apoptosis- Apoptosis, Anti-oncogene,3248 7216 associated speck- Alternative splicing like protein containinga CARD NM_013259 NP25 neuronal protein 3249 7217 NM_013272 SLC21A11solute carrier organic Transmembrane, Transport, Ion 3250 7218 aniontransporter transport, Glycoprotein family, member 3A1 NM_013285HUMAUANTIG nucleolar GTPase GTP-binding, Nuclear protein 3251 7219NM_013286 KIAA0800 chromosome 3p21.1 Hypothetical protein 3252 7220 genesequence NM_013289 KIR3DL1 killer cell Receptor, Immunoglobulin domain,3253 7221 immunoglobulin-like Glycoprotein, Signal, receptor, threeTransmembrane, Repeat, Multigene domains, long family, Polymorphism,3D-structure, cytoplasmic tail, 1 Alternative splicing NM_013296 MCLCLGN protein Hypothetical protein, Repeat, TPR 3254 7222 repeat,Phosphorylation NM_013300 HSU79274 protein predicted by Hypotheticalprotein 3255 7223 clone 23733 NM_013301 HSU79303 protein predicted byHypothetical protein 3256 7224 clone 23882 NM_013312 HOOK2 hook homolog2 Hypothetical protein 3257 7225 (Drosophila) NM_013319 TERE1transitional epithelia 3258 7226 response protein NM_013323 SNX11sorting nexin 11 Transport, Protein transport 3259 7227 NM_013328 P5CR2pyrroline 5- Hypothetical protein 3260 7228 carboxylate reductaseisoform NM_013330 NME7 non-metastatic cells Transferase, Kinase,ATP-binding, 3261 7229 7, protein expressed Sodium/potassium transport,in (nucleoside- Transmembrane, Glycoprotein, diphosphate kinase)Multigene family, Signal-anchor, Alternative splicing NM_013341 PTD004hypothetical protein GTP-binding, Alternative splicing 3262 7230 PTD004NM_013351 TBX21 T-box 21 Transcription regulation, DNA- 3263 7231binding, Nuclear protein, Activator NM_013354 CNOT7 CCR4-NOTTranscription regulation, Repressor, 3264 7232 transcription Nuclearprotein, Hypothetical protein complex, subunit 7 NM_013363 PCOLCE2procollagen C- Collagen 3265 7233 endopeptidase enhancer 2 NM_013364PNMA3 paraneoplastic Hypothetical protein 3266 7234 antigen MA3NM_013368 RBT1 RPA-binding trans- Hypothetical protein 3267 7235activator NM_013382 POMT2 protein-O- Transferase, Glycosyltransferase,3268 7236 mannosyltransferase 2 Endoplasmic reticulum, Transmembrane,Glycoprotein, Repeat, Alternative splicing NM_013383 TCFL4 transcriptionfactor- Transcription regulation, Repressor, 3269 7237 like 4 Nuclearprotein, DNA-binding, Alternative splicing, Receptor NM_013392 NRBPnuclear receptor Hypothetical protein, ATP-binding, 3270 7238 bindingprotein Transferase, Nuclear protein, Receptor NM_013395 AD013 Homosapiens Hypothetical protein, 3271 7239 proteinx0008 Transmembrane(AD013) mRNA, complete cds. NM_013403 STRN4 striatin, calmodulinCalmodulin-binding, Repeat, WD 3272 7240 binding protein 4 repeat,Coiled coil NM_013412 RABL2A RAB, member of Hypothetical protein,GTP-binding, 3273 7241 RAS oncogene Alternative splicing family-like 2ANM_013416 NCF4 neutrophil cytosolic SH3 domain, Alternative splicing,3274 7242 factor 4, 40 kDa 3D-structure NM_013421 GGT1 gamma-Glutathione biosynthesis, 3275 7243 glutamyltransferase 1 Transferase,Acyltransferase, Signal-anchor, Transmembrane, Zymogen, Glycoprotein,Sialic acid, Alternative splicing, Alternative promoter usage NM_013430GGT1 gamma- Glutathione biosynthesis, 3276 7244 glutamyltransferase 1Transferase, Acyltransferase, Signal-anchor, Transmembrane, Zymogen,Glycoprotein, Sialic acid, Alternative splicing, Alternative promoterusage NM_013439 PILR(ALPHA) paired Receptor 3277 7245 immunoglobin-liketype 2 receptor alpha NM_013440 PILR(BETA) paired Meiosis, Cell cycle,Chromosome 3278 7246 immunoglobin-like partition, Nuclear protein,Alternative type 2 receptor beta splicing, Hypothetical protein,Receptor NM_013444 UBQLN2 ubiquilin 2 Hypothetical protein 3279 7247NM_013448 BAZ1A bromodomain Transcription regulation, 3280 7248 adjacentto zinc Bromodomain, Zinc-finger, Coiled finger domain, 1A coil, Nuclearprotein, Alternative splicing NM_013940 OR10H1 olfactory receptor, 32817249 family 10, subfamily H, member 1 NM_013943 CLIC4 chlorideintracellular Hypothetical protein, Ionic channel, 3282 7250 channel 4Ion transport, Chloride channel, Voltage-gated channel NM_013951 PAX8paired box gene 8 DNA-binding, Developmental 3283 7251 protein, Nuclearprotein, Paired box, Transcription, Transcription regulation,Differentiation, Alternative splicing, Disease mutation, PolymorphismNM_013956 NRG1 neuregulin 1 EGF-like domain, Growth factor, 3284 7252Transmembrane, Multigene family, Alternative splicing, Immunoglobulindomain, Glycoprotein, Polymorphism, 3D-structure, Chromosomaltranslocation NM_013974 DDAH2 dimethylarginine Hydrolase 3285 7253dimethylaminohydrolase 2 NM_013975 LIG3 ligase III, DNA, ATP- DNArepair, DNA replication, DNA 3286 7254 dependent recombination, Celldivision, Ligase, ATP-binding, Zinc-finger, Nuclear protein, Alternativesplicing, 3D- structure, Hypothetical protein NM_013979 BNIP1BCL2/adenovirus Apoptosis, Alternative splicing, 3287 7255 E1B 19 kDaTransmembrane interacting protein 1 NM_013992 PAX8 paired box gene 8DNA-binding, Developmental 3288 7256 protein, Nuclear protein, Pairedbox, Transcription, Transcription regulation, Differentiation,Alternative splicing, Disease mutation, Polymorphism NM_013995 LAMP2lysosomal- Transmembrane, Glycoprotein, 3289 7257 associated Lysosome,Signal, Alternative membrane protein 2 splicing, Polymorphism NM_014000VCL vinculin Cell adhesion, Actin-binding, 3290 7258 Cytoskeleton,Structural protein, Phosphorylation, Repeat, Alternative splicing,Lipoprotein NM_014011 SOCS5 suppressor of SH2 domain, Growth regulation,3291 7259 cytokine signaling 5 Signal transduction inhibitor NM_014018MRPS28 mitochondrial Ribosomal protein, Mitochondrion 3292 7260ribosomal protein S28 NM_014029 RAC2 ras-related C3 GTP-binding,Prenylation, 3293 7261 botulinum toxin Lipoprotein, 3D-structuresubstrate 2 (rho family, small GTP binding protein Rac2) NM_014030 GIT1G protein-coupled Hypothetical protein, GTPase 3294 7262 receptorkinase- activation, Repeat, ANK repeat, interactor 1 Zinc-fingerNM_014038 BZW2 basic leucine zipper Hypothetical protein 3295 7263 andW2 domains 2 NM_014042 DKFZP564M082 DKFZP564M082 Hypothetical protein3296 7264 protein NM_014050 MRPL42 mitochondrial Ribosomal protein,Mitochondrion 3297 7265 ribosomal protein L42 NM_014051 PTD011transmembrane Transmembrane 3298 7266 protein 14A NM_014052 GW128 GW128protein 3299 7267 NM_014055 CDV-1 carnitine deficiency- Hypotheticalprotein 3300 7268 associated gene expressed in ventricle 1 NM_014056HIG1 likely ortholog of Hypothetical protein 3301 7269 mouse hypoxiainduced gene 1 NM_014060 MCT-1 malignant T cell 3302 7270 amplifiedsequence 1 NM_014061 MAGEH1 APR-1 protein Antigen 3303 7271 NM_014062ART-4 likely ortholog of Hypothetical protein 3304 7272 mouse nin onebinding protein NM_014063 HIP-55 src homology 3 Hypothetical protein,SH3 domain 3305 7273 domain-containing protein HIP-55 NM_014078 MRPL13mitochondrial Ribosomal protein, Mitochondrion 3306 7274 ribosomalprotein L13 NM_014080 DUOX2 dual oxidase 2 Peroxidase 3307 7275NM_014147 CAPRI HSPC047 protein GTPase activation, Repeat 3308 7276NM_014165 C6orf66 chromosome 6 open 3309 7277 reading frame 66 NM_014170HSPC135 HSPC135 protein Hypothetical protein 3310 7278 NM_014175 MRPL15mitochondrial Hypothetical protein 3311 7279 ribosomal protein L15NM_014177 HSPC154 HSPC154 protein 3312 7280 NM_014180 MRPL22mitochondrial Hypothetical protein, Ribosomal 3313 7281 ribosomalprotein protein L22 NM_014182 ORMDL2 ORM1-like 2 (S. cerevisiae)Hypothetical protein, Nuclear 3314 7282 protein, DNA-binding,Transcription, Transcription regulation, Translation regulation,Receptor NM_014184 HSPC163 HSPC163 protein Hypothetical protein, 33157283 Transmembrane NM_014204 BOK Homo sapiens Bcl-2 3316 7284 relatedovarian killer (BOK) mRNA, complete cds. NM_014207 CD5 CD5 antigen(p56-62) Signal, Transmembrane, 3317 7285 Glycoprotein, T-cell, RepeatNM_014214 IMPA2 inositol(myo)-1(or 4)- Hydrolase 3318 7286monophosphatase 2 NM_014216 ITPK1 inositol 1,3,4- Kinase, Hypotheticalprotein 3319 7287 triphosphate 5/6 kinase NM_014221 MTCP1 mature T-cellProto-oncogene, Mitochondrion, 3320 7288 proliferation 1 Alternativesplicing, Chromosomal translocation, 3D-structure NM_014223 NFYC nucleartranscription Transcription regulation, DNA- 3321 7289 factor Y, gammabinding, Activator, Nuclear protein, Alternative splicing, 3D-structureNM_014225 PPP2R1A protein phosphatase Hypothetical protein, Multigene3322 7290 2 (formerly 2A), family, Acetylation, Repeat, regulatorysubunit A Polymorphism, 3D-structure (PR 65), alpha isoform NM_014231VAMP1 vesicle-associated Mitochondrion, Synapse, 3323 7291 membraneprotein 1 Synaptosome, Transmembrane, (synaptobrevin 1) Coiled coil,Alternative splicing, Multigene family NM_014232 VAMP2vesicle-associated Hypothetical protein, Synapse, 3324 7292 membraneprotein 2 Synaptosome, Transmembrane, (synaptobrevin 2) Coiled coil,Acetylation, Multigene family, 3D-structure NM_014239 EIF2B2 eukaryoticInitiation factor, Protein biosynthesis, 3325 7293 translationinitiation Disease mutation factor 2B, subunit 2 beta, 39 kDa NM_014241PTPLA protein tyrosine ATP-binding, Chaperone 3326 7294 phosphatase-like(proline instead of catalytic arginine), member a NM_014242 ZNF237 zincfinger protein 3327 7295 237 NM_014245 RNF7 ring finger protein 7 Ublconjugation pathway, Zinc, Zinc- 3328 7296 finger, Metal-binding,Phosphorylation, Alternative splicing NM_014252 SLC25A15 solute carrierfamily Mitochondrion, Inner membrane, 3329 7297 25 (mitochondrialRepeat, Transmembrane, Transport, carrier; ornithine Disease mutation,Polymorphism transporter) member 15 NM_014253 ODZ1 odz, odd Oz/ten-mEGF-like domain 3330 7298 homolog 1(Drosophila) NM_014254 TMEM5transmembrane Transmembrane 3331 7299 protein 5 NM_014268 MAPRE2microtubule- T-cell 3332 7300 associated protein, RP/EB family, member 2NM_014280 DNAJC8 DnaJ (Hsp40) Chaperone 3333 7301 homolog, subfamily C,member 8 NM_014292 CBX6 chromobox homolog 6 Chromatin regulator, Nuclear3334 7302 protein, Transcription regulation, Repressor NM_014297 YF13H12ethylmalonic 3335 7303 encephalopathy 1 NM_014306 HSPC117 hypotheticalprotein Hypothetical protein 3336 7304 HSPC117 NM_014313 SMP1 smallmembrane Transmembrane, Polymorphism 3337 7305 protein 1 NM_014326 DAPK2death-associated Transferase, Serine/threonine- 3338 7306 protein kinase2 protein kinase, Calmodulin-binding, Phosphorylation, ATP-binding,Apoptosis NM_014330 PPP1R15A protein phosphatase Hypothetical protein3339 7307 1, regulatory (inhibitor) subunit 15A NM_014335 CRI1CREBBP/EP300 Hypothetical protein 3340 7308 inhibitory protein 1NM_014339 IL17R interleukin 17 Receptor, Transmembrane, Signal, 33417309 receptor Glycoprotein NM_014341 MTCH1 mitochondrial carrier 33427310 homolog 1 (C. elegans) NM_014343 CLDN15 claudin 15 Tight junction,Transmembrane 3343 7311 NM_014350 GG2-1 TNF-induced protein 3344 7312NM_014357 XP5 small proline rich-like 3345 7313 (epidermaldifferentiation complex) 1B NM_014359 OPTC opticin Glycoprotein,Extracellular matrix, 3346 7314 Signal, Repeat, Leucine-rich repeat,Sulfation NM_014362 HIBCH 3-hydroxyisobutyryl- Hydrolase 3347 7315Coenzyme A hydrolase NM_014366 E2IG3 nucleostemin Hypothetical protein3348 7316 NM_014373 GPCR1 G protein-coupled Receptor 3349 7317 receptor160 NM_014381 MLH3 mutL homolog 3 (E. coli) DNA repair, Nuclear protein,3350 7318 Polymorphism, Alternative splicing, Hereditary nonpolyposiscolorectal cancer, Disease mutation, Hypothetical protein NM_014399NET-6 transmembrane 4 Glycoprotein, Transmembrane 3351 7319 superfamilymember 13 NM_014403 SIAT7D sialyltransferase 7D Transferase,Glycosyltransferase, 3352 7320 ((alpha-N- Glycoprotein, Transmembrane,acetylneuraminyl- Signal-anchor, Golgi stack 2,3-beta-galactosyl-1,3)-N-acetyl galactosaminide alpha-2,6- sialyltransferase) NM_014413HRI heme-regulated Transferase, Kinase, 3353 7321 initiation factor 2-Serine/threonine-protein kinase, alpha kinase Protein synthesisinhibitor, ATP- binding, Repeat, Phosphorylation, Alternative splicing,Polymorphism, Protein biosynthesis NM_014425 INVS inversin ANK repeat,Repeat 3354 7322 NM_014426 SNX5 sorting nexin 5 Transport, Proteintransport, 3355 7323 Hypothetical protein NM_014430 CIDEB celldeath-inducing Apoptosis, 3D-structure, RNA- 3356 7324 DFFA-likeeffector b binding, Repeat, G-protein coupled receptor, Transmembrane,Glycoprotein NM_014434 NR1 NADPH-dependent 3357 7325 FMN and FADcontaining oxidoreductase NM_014437 SLC39A1 solute carrier familyTransport, Zinc transport, 3358 7326 39 (zinc transporter),Transmembrane member 1 NM_014446 MIBP integrin beta 1 3359 7327 bindingprotein 3 NM_014450 SIT SHP2-interacting Signal 3360 7328 transmembraneadaptor protein NM_014453 BC-2 putative breast 3361 7329 adenocarcinomamarker (32 kD) NM_014465 SULT1B1 sulfotransferase Hypothetical protein,Transferase 3362 7330 family, cytosolic, 1B, member 1 NM_014473 HSA9761putative rRNA processing, Transferase, 3363 7331 dimethyladenosineMethyltransferase transferase NM_014481 APEX2 APEX nuclease Endonuclease3364 7332 (apurinic/apyrimidinic endonuclease) 2 NM_014499 P2RY10purinergic receptor Receptor, Transmembrane 3365 7333 P2Y, G-proteincoupled, 10 NM_014503 DRIM down-regulated in 3366 7334 metastasisNM_014517 UBP1 upstream binding Hypothetical protein 3367 7335 protein 1(LBP-1a) NM_014520 MYBBP1A MYB binding protein Hypothetical protein 33687336 (P160) 1a NM_014575 SCHIP1 schwannomin Hypothetical protein 33697337 interacting protein 1 NM_014593 CGBP CpG binding proteinHypothetical protein, Transcription 3370 7338 regulation, Activator,DNA-binding, Zinc-finger, Metal-binding, Coiled coil, Nuclear proteinNM_014624 S100A6 S100 calcium Mitogen, Cell cycle, Calcium-binding, 33717339 binding protein A6 Polymorphism, 3D-structure (calcyclin) NM_014630KIAA0211 KIAA0211 gene Hypothetical protein, Transcription 3372 7340product regulation, DNA-binding, Zinc-finger, Metal-binding, Nuclearprotein, Repeat NM_014638 KIAA0450 KIAA0450 gene Hypothetical protein3373 7341 product NM_014639 KIAA0372 KIAA0372 Hypothetical protein 33747342 NM_014659 KIAA0377 KIAA0377 gene Hypothetical protein 3375 7343product NM_014671 KIAA0010 ubiquitin-protein Hypothetical protein,Ligase 3376 7344 isopeptide ligase (E3) NM_014675 KIAA0445 ciliaryrootlet coiled- Hypothetical protein 3377 7345 coil, rootletin NM_014678KIAA0685 KIAA0685 Hypothetical protein 3378 7346 NM_014684 KIAA0373KIAA0373 gene Hypothetical protein, Coiled coil 3379 7347 productNM_014685 HERPUD1 homocysteine- Hypothetical protein, Unfolded 3380 7348inducible, protein response, Endoplasmic endoplasmic reticulum,Transmembrane, reticulum stress- Alternative splicing inducible,ubiquitin- like domain member 1 NM_014688 RNTRE USP6 N-terminal likeHypothetical protein 3381 7349 NM_014698 KIAA0792 KIAA0792 geneHypothetical protein 3382 7350 product NM_014699 KIAA0296 KIAA0296 geneHypothetical protein, Transcription 3383 7351 product regulation,DNA-binding, Zinc-finger, Metal-binding, Nuclear protein, RepeatNM_014707 HDAC9 histone deacetylase 9 Hydrolase, Nuclear protein, 33847352 Chromatin regulator, Transcription regulation, Repressor,Alternative splicing, Hypothetical protein NM_014710 KIAA0443 Gprotein-coupled Hypothetical protein 3385 7353 receptor-associatedsorting protein NM_014716 CENTB1 centaurin, beta 1 GTPase activation,Repeat, ANK 3386 7354 repeat, Zinc-finger NM_014718 CLSTN3 calsyntenin 3Cell adhesion, Glycoprotein, 3387 7355 Transmembrane, Calcium-binding,Repeat, Signal NM_014724 ZNF305 zinc finger protein Transcriptionregulation, DNA- 3388 7356 305 binding, Zinc-finger, Metal-binding,Nuclear protein, Repeat NM_014727 WBP7 myeloid/lymphoid or DNA-binding,Bromodomain, 3389 7357 mixed-lineage Nuclear protein, Zinc-finger,Metal- leukemia 4 binding, Transcription regulation, Alternativesplicing, Repeat NM_014729 TOX thymus high mobility Hypothetical protein3390 7358 group box protein TOX NM_014732 KIAA0513 KIAA0513 geneHypothetical protein 3391 7359 product NM_014735 KIAA0215 PHD fingerprotein Zinc-finger 3392 7360 16 NM_014737 RASSF2 Ras associationHypothetical protein 3393 7361 (RaIGDS/AF-6) domain family 2 NM_014739BTF Bcl-2-associated Hypothetical protein 3394 7362 transcription factorNM_014740 KIAA0111 DEAD (Asp-Glu-Ala- ATP-binding, RNA-binding, DNA-3395 7363 Asp) box polypeptide binding, Helicase, Nuclear protein, 48rRNA processing NM_014750 DLG7 discs, large homolog Hypothetical protein3396 7364 7 (Drosophila) NM_014751 MTSS1 metastasis Cytoskeleton,Actin-binding, Coiled 3397 7365 suppressor 1 coil, Anti-oncogene,Alternative splicing NM_014753 KIAA0187 BMS1-like, ribosome Ribosomebiogenesis, Nuclear 3398 7366 assembly protein protein, ATP-binding(yeast) NM_014763 MRPL19 mitochondrial Ribosomal protein, Mitochondrion,3399 7367 ribosomal protein Transit peptide L19 NM_014764 DAZAP2 DAZassociated Hypothetical protein 3400 7368 protein 2 NM_014765 TOMM20-translocase of outer Transport, Protein transport, Outer 3401 7369PENDING mitochondrial membrane, Mitochondrion, membrane 20 Transmembranehomolog (yeast) NM_014767 SPOCK2 sparc/osteonectin, Extracellularmatrix, Proteoglycan, 3402 7370 cwcv and kazal-like Heparan sulfate,Glycoprotein, domains Calcium-binding, Signal proteoglycan (testican) 2NM_014776 GIT2 G protein-coupled GTPase activation, Repeat, ANK 34037371 receptor kinase- repeat, Zinc-finger, Alternative interactor 2splicing, Hypothetical protein NM_014792 KIAA0125 KIAA0125 Hypotheticalprotein 3404 7372 NM_014807 KIAA0285 KIAA0285 gene Hypothetical protein3405 7373 product NM_014808 FARP2 FERM, RhoGEF and Hypothetical protein3406 7374 pleckstrin domain protein 2 NM_014815 TRAP100 thyroid hormoneTranscription regulation, Zinc-finger, 3407 7375 receptor-associatedRepeat, ATP-binding, Nuclear protein (100 kDa) protein NM_014820 TOMM70Atranslocase of outer Mitochondrion, Outer membrane, 3408 7376mitochondrial Transmembrane, Repeat, TPR membrane 70 repeat homolog A(yeast) NM_014830 KIAA0352 KIAA0352 gene Hypothetical protein,Transcription 3409 7377 product regulation, DNA-binding, Zinc-finger,Metal-binding, Nuclear protein, Repeat NM_014835 OSBPL2 oxysterolbinding Lipid transport, Transport, 3410 7378 protein-like 2 Alternativesplicing NM_014838 ZBED4 zinc finger, BED Repeat, Zinc-finger 3411 7379domain containing 4 NM_014844 KIAA0329 KIAA0329 Hypothetical protein3412 7380 NM_014846 KIAA0196 KIAA0196 gene Hypothetical protein 34137381 product NM_014861 KIAA0703 KIAA0703 gene Hydrolase, Calciumtransport, 3414 7382 product Transmembrane, Phosphorylation,ATP-binding, Metal-binding, Magnesium, Calcium-binding, Multigene familyNM_014863 GALNAC4S- B cell RAG Hypothetical protein, Transferase 34157383 6ST associated protein NM_014865 CNAP1 chromosome DNA condensation,Mitosis, Cell 3416 7384 condensation-related cycle, Nuclear protein,SMC-associated Phosphorylation protein 1 NM_014869 KIAA0763 KIAA0763gene Hypothetical protein 3417 7385 product NM_014872 KIAA0354 zincfinger and BTB Hypothetical protein, Metal-binding, 3418 7386 domaincontaining 5 Zinc, Zinc-finger NM_014873 KIAA0205 KIAA0205 geneHypothetical protein, Phospholipid 3419 7387 product biosynthesis,Transferase, Acyltransferase, Transmembrane NM_014874 MFN2 mitofusin 2Hypothetical protein 3420 7388 NM_014878 KIAA0020 minor Hypotheticalprotein, RNA-binding, 3421 7389 histocompatibility Repeat, Nuclearprotein antigen HA-8 NM_014882 KIAA0053 KIAA0053 gene Hypotheticalprotein 3422 7390 product NM_014886 YR-29 TGF beta-inducible Nuclearprotein 3423 7391 nuclear protein 1 NM_014888 FAM3C family with sequenceSignal 3424 7392 similarity 3, member C NM_014889 PITRM1 pitrilysinMetalloprotease, Protease, 3425 7393 metalloproteinase 1 Hypotheticalprotein NM_014897 KIAA0924 KIAA0924 protein Hypothetical protein,Metal-binding, 3426 7394 Nuclear protein, Zinc, Zinc-finger NM_014899RHOBTB3 Rho-related BTB Repeat 3427 7395 domain containing 3 NM_014902KIAA0964 disks large- Membrane, Alternative splicing 3428 7396associated protein 4 NM_014907 KIAA0967 KIAA0967 protein Hypotheticalprotein 3429 7397 NM_014913 KIAA0863 KIAA0863 protein Hypotheticalprotein, Metal-binding, 3430 7398 Zinc, Zinc-finger NM_014915 KIAA1074KIAA1074 protein ANK repeat, Repeat, Hypothetical 3431 7399 proteinNM_014929 KIAA0971 KIAA0971 protein Hypothetical protein 3432 7400NM_014931 KIAA1115 KIAA1115 protein Hypothetical protein 3433 7401NM_014937 SAC2 inositol Hypothetical protein 3434 7402 polyphosphate-5-phosphatase F NM_014940 KIAA0872 HSV-1 stimulation- Hypothetical protein3435 7403 related gene 1 NM_014944 CLSTN1 calsyntenin 1 Cell adhesion,Glycoprotein, 3436 7404 Transmembrane, Calcium-binding, Repeat, SignalNM_014947 KIAA1041 KIAA1041 protein Hypothetical protein, Transcription3437 7405 regulation, DNA-binding, Nuclear protein NM_014949 KIAA0907KIAA0907 protein Hypothetical protein 3438 7406 NM_014953 DIS3 mitoticcontrol Exosome, Hydrolase, Nuclease, 3439 7407 protein dis3 homologExonuclease, rRNA processing, Nuclear protein, RNA-binding, Hypotheticalprotein NM_014965 KIAA1042 OGT(O-Glc-NAc Glycoprotein, Coiled coil, 34407408 transferase)- Hypothetical protein interacting protein 106 KDaNM_014966 DDX30 DEAH (Asp-Glu-Ala- ATP-binding, Helicase, Hydrolase,3441 7409 His) box polypeptide Hypothetical protein 30 NM_014967KIAA1018 KIAA1018 protein Hypothetical protein 3442 7410 NM_014977ACINUS apoptotic chromatin Apoptosis, Nuclear protein, 3443 7411condensation Alternative splicing inducer in the nucleus NM_015057KIAA0916 protein associated Hypothetical protein 3444 7412 with MycNM_015156 RCOR REST corepressor DNA-binding, Nuclear protein, 3445 7413Hypothetical protein NM_015239 AGTPBP1 ATP/GTP binding Hypotheticalprotein 3446 7414 protein 1 NM_015310 EFA6R ADP-ribosylationHypothetical protein, Guanine- 3447 7415 factor guanine nucleotidereleasing factor nucleotide factor 6 NM_015361 R3HDM R3H domain (bindsHypothetical protein 3448 7416 single-stranded nucleic acids) containingNM_015368 PANX1 pannexin 1 Gap junction, Transmembrane, 3449 7417Polymorphism NM_015379 BRI3 brain protein I3 Transmembrane 3450 7418NM_015383 DJ328E19.C1.1 hypothetical protein Hypothetical protein 34517419 DJ328E19.C1.1 NM_015392 NPDC1 neural proliferation, Hypotheticalprotein, Signal, 3452 7420 differentiation and Transmembrane control, 1NM_015400 DKFZP586N0721 DKFZP586N0721 Hypothetical protein 3453 7421protein NM_015420 DKFZP564O0463 DKFZP564O0463 Repeat, WD repeat,Mitochondrion, 3454 7422 protein Inner membrane, Transmembrane,Transport, Hypothetical protein NM_015462 DKFZP586L0724 DKFZP586L0724Hypothetical protein 3455 7423 protein NM_015492 DKFZP434H132DKFZP434H132 Hypothetical protein 3456 7424 protein NM_015515 KRT23keratin 23 (histone Hypothetical protein, Intermediate 3457 7425deacetylase filament, Coiled coil, Keratin inducible) NM_015524 C6orf4chromosome 6 open Alternative splicing 3458 7426 reading frame 4NM_015527 DKFZP434P1750 DKFZP434P1750 Hypothetical protein 3459 7427protein NM_015530 GORASP2 golgi reassembly Hypothetical protein 34607428 stacking protein 2, 55 kDa NM_015556 KIAA0440 signal-inducedHypothetical protein 3461 7429 proliferation- associated 1 like 1NM_015599 PGM3 phosphoglucomutase 3 Hypothetical protein, Isomerase,3462 7430 Phosphorylation, Polymorphism NM_015610 DKFZP434J154DKFZP434J154 Repeat, WD repeat, Hypothetical 3463 7431 protein proteinNM_015629 PRPF31 TCF3 (E2A) fusion Hypothetical protein 3464 7432partner (in childhood Leukemia) NM_015640 PAI-RBP1 PAI-1 mRNA-bindingHypothetical protein 3465 7433 protein NM_015644 ARPC4 actin relatedprotein Cytoskeleton, Hypothetical protein, 3466 7434 2/3 complex,subunit Ligase 4, 20 kDa NM_015654 DKFZP564C103 DKFZP564C103Hypothetical protein 3467 7435 protein NM_015684 ATP5S ATP synthase, H+Hydrogen ion transport, CF(0), 3468 7436 transporting, Mitochondrion,Transit peptide, mitochondrial F0 Hypothetical protein complex, subunits (factor B) NM_015696 CL683 glutathione Hypothetical protein, 3469 7437peroxidase 6 Oxidoreductase, Peroxidase, Signal NM_015699 DJ159A19.3hypothetical protein Hypothetical protein 3470 7438 DJ159A19.3 NM_015711GLTSCR1 glioma tumor 3471 7439 suppressor candidate region gene 1NM_015722 CALCYON calcyon protein Transmembrane, Glycoprotein 3472 7440NM_015836 WARS2 tryptophanyl tRNA Aminoacyl-tRNA synthetase, Protein3473 7441 synthetase 2 biosynthesis, Ligase, ATP-binding,(mitochondrial) Mitochondrion, Transit peptide NM_015838 FCN2 ficolinLectin, Collagen, Repeat, 3474 7442 (collagen/fibrinogen Glycoprotein,Signal, Multigene domain containing family lectin) 2 (hucolin) NM_015839FCN2 ficolin Lectin, Collagen, Repeat, 3475 7443 (collagen/fibrinogenGlycoprotein, Signal, Multigene domain containing family lectin) 2(hucolin) NM_015853 LOC51035 ORF Hypothetical protein 3476 7444NM_015855 WIT-1 Wilms tumor Polymorphism 3477 7445 associated proteinNM_015868 KIR2DL3 killer cell Receptor, Immunoglobulin domain, 3478 7446immunoglobulin-like Glycoprotein, Signal, receptor, two Transmembrane,Repeat, Multigene domains, long family, Polymorphism, 3D-structure,cytoplasmic tail, 3 Alternative splicing NM_015872 ZFP67 zinc fingerprotein 67 Metal-binding, Zinc, Zinc-finger 3479 7447 homolog (mouse)NM_015905 TIF1 transcriptional Elongation factor, Protein 3480 7448intermediary factor 1 biosynthesis, GTP-binding, Methylation, Multigenefamily, Transcription regulation, Repressor, DNA-binding, Bromodomain,Zinc- finger, Alternative splicing, Nuclear protein, Coiled coil, RepeatNM_015907 LAP3 leucine Hydrolase, Aminopeptidase, 3481 7449aminopeptidase 3 Acetylation, Zinc, Magnesium, Manganese NM_015908 ARS2arsenate resistance Hypothetical protein, Alternative 3482 7450 proteinARS2 splicing NM_015932 C13orf12 chromosome 13 Hypothetical protein 34837451 open reading frame 12 NM_015942 LOC51001 CGI-12 proteinHypothetical protein 3484 7452 NM_015945 OVCOV1 solute carrier familyHypothetical protein 3485 7453 35, member C2 NM_015956 MRPL4mitochondrial Ribosomal protein 3486 7454 ribosomal protein L4 NM_015958LOC51611 CGI-30 protein Transferase, Methyltransferase, 3487 7455Alternative splicing, Hypothetical protein NM_015959 LOC51075thioredoxin-related Hypothetical protein 3488 7456 transmembrane protein2 NM_015963 LOC51078 THAP domain Zinc-finger, DNA-binding 3489 7457containing 4 NM_015967 PTPN22 protein tyrosine Hydrolase, Alternativesplicing, 3490 7458 phosphatase, non- Hypothetical protein receptor type22 (lymphoid) NM_015971 MRPS7 mitochondrial Ribosomal protein 3491 7459ribosomal protein S7 NM_015984 UCHL5 ubiquitin carboxyl- Hypotheticalprotein, Ubl conjugation 3492 7460 terminal hydrolase pathway,Hydrolase, Thiol protease, L5 Proteasome, Alternative splicing,Polymorphism NM_015999 LOC51094 adiponectin receptor 1 Fatty acidmetabolism, Lipid 3493 7461 metabolism, Receptor, TransmembraneNM_016006 CGI-58 abhydrolase domain Hypothetical protein 3494 7462containing 5 NM_016017 UCHL5 ubiquitin carboxyl- Hypothetical protein,Hydrolase, Ubl 3495 7463 terminal hydrolase conjugation pathway, Thiolprotease, L5 Proteasome, Alternative splicing, Polymorphism NM_016022LOC51107 likely ortholog of C. elegans Transmembrane, Golgi stack, 34967464 anterior Endoplasmic reticulum, Alternative pharynx defective 1Asplicing NM_016026 RDH11 retinol Oxidoreductase, NADP, Signal- 3497 7465dehydrogenase 11 anchor, Transmembrane, (all-trans and 9-cis)Endoplasmic reticulum, Alternative splicing NM_016039 LOC51637chromosome 14 Hypothetical protein 3498 7466 open reading frame 166NM_016045 C20orf45 chromosome 20 3499 7467 open reading frame 45NM_016052 LOC51018 CGI-115 protein 3500 7468 NM_016055 MRPL48mitochondrial Ribosomal protein, Mitochondrion 3501 7469 ribosomalprotein L48 NM_016056 LOC51643 CGI-119 protein Transmembrane,Polymorphism 3502 7470 NM_016058 LOC51002 CGI-121 protein 3503 7471NM_016064 PILB methionine sulfoxide Hypothetical protein 3504 7472reductase B NM_016072 LOC51026 CGI-141 protein Hypothetical protein,3505 7473 Transmembrane NM_016075 C13orf9 chromosome 13 Hypotheticalprotein 3506 7474 open reading frame 9 NM_016082 CDK5RAP1 CDK5regulatory Alternative splicing 3507 7475 subunit associated protein 1NM_016093 RPL26L1 ribosomal protein Ribosomal protein 3508 7476 L26-like1 NM_016096 LOC51123 HSPC038 protein Metal-binding, Zinc, Zinc-finger3509 7477 NM_016101 HSPC031 comparative gene Hypothetical protein 35107478 identification transcript 37 NM_016120 RNF12 ring finger protein 12Hypothetical protein, Metal-binding, 3511 7479 Zinc, Zinc-finger,Transcription regulation NM_016122 LOC51134 NY-REN-58 antigen 3512 7480NM_016126 LOC51668 HSPCO34 protein 3513 7481 NM_016127 MGC8721hypothetical protein Hypothetical protein 3514 7482 MGC8721 NM_016129COPS4 COP9 constitutive Hypothetical protein 3515 7483 photomorphogenichomolog subunit 4 (Arabidopsis) NM_016143 NSFL1C NSFL1 (p97)Hypothetical protein 3516 7484 cofactor (p47) NM_016167 RANBP9 retinoicacid Hypothetical protein 3517 7485 repressible protein NM_016175 SQSTM1truncated calcium Hypothetical protein 3518 7486 binding proteinNM_016183 C1orf33 chromosome 1 open Hypothetical protein, Ribosomal 35197487 reading frame 33 protein NM_016184 CLECSF6 C-type (calciumReceptor, Lectin 3520 7488 dependent, carbohydrate- recognition domain)lectin, superfamily member 6 NM_016187 BIN2 bridging integrator 2Hypothetical protein 3521 7489 NM_016194 GNB5 guanine nucleotide Repeat,WD repeat, Transducer, 3522 7490 binding protein (G Alternativesplicing, Multigene family, protein), beta 5 Hypothetical proteinNM_016199 LSM7 LSM7 homolog, U6 Nuclear protein, Ribonucleoprotein, 35237491 small nuclear RNA mRNA splicing, mRNA processing, associated (S.cerevisiae) RNA-binding NM_016202 LOC51157 LDL induced EC Metal-binding,Zinc, Zinc-finger 3524 7492 protein NM_016207 CPSF3 cleavage and mRNAprocessing, Nuclear protein, 3525 7493 polyadenylation RNA-bindingspecific factor 3, 73 kDa NM_016208 VPS28 vacuolar protein Transport,Protein transport 3526 7494 sorting 28 (yeast) NM_016214 COL18A1collagen, type XVIII, Collagen, Extracellular matrix, 3527 7495 alpha 1Connective tissue, Repeat, Hydroxylation, Cell adhesion, Glycoprotein,Signal, Alternative splicing, Polymorphism, 3D-structure NM_016221 DCTN4dynactin 4 (p62) Hypothetical protein 3528 7496 NM_016229 LOC51700cytochrome b5 Hypothetical protein 3529 7497 reductase b5R.2 NM_016237ANAPC5 anaphase promoting Ubl conjugation pathway, Cell cycle, 3530 7498complex subunit 5 Cell division, Mitosis, Repeat, TPR repeat,Alternative splicing NM_016258 HGRG8 high-glucose- 3531 7499 regulatedprotein 8 NM_016271 RNF138 ring finger protein Hypothetical protein,Metal-binding, 3532 7500 138 Zinc, Zinc-finger NM_016274 CKIP-1 CK2interacting Hypothetical protein 3533 7501 protein 1; HQ0024c proteinNM_016283 TAF9 TAF9 RNA ATP-binding, Transcription 3534 7502 polymeraseII, TATA regulation, Nuclear protein, box binding protein Polymorphism,Hypothetical protein, (TBP)-associated Cell cycle factor, 32 kDaNM_016293 BIN2 bridging integrator 2 Hypothetical protein 3535 7503NM_016299 HSP70-4 likely ortholog of ATP-binding 3536 7504 mouse heatshock protein, 70 kDa 4 NM_016304 C15orf15 chromosome 15 Ribosomalprotein 3537 7505 open reading frame 15 NM_016306 DNAJB11 DnaJ (Hsp40)Chaperone, Endoplasmic reticulum, 3538 7506 homolog, subfamily Signal,Polymorphism B, member 11 NM_016309 LCMT1 leucine carboxyl Hypotheticalprotein, 3539 7507 methyltransferase 1 Methyltransferase, TransferaseNM_016312 WBP11 WW domain binding Hypothetical protein 3540 7508 protein11 NM_016316 REV1L REV1-like (yeast) Transferase, Integrin, Hypothetical3541 7509 protein NM_016326 CKLF chemokine-like Chemotaxis, Cytokine,3542 7510 factor Transmembrane, Alternative splicing NM_016327 UPB1ureidopropionase, Hydrolase, Allosteric enzyme, Zinc 3543 7511 betaNM_016331 LOC51193 zinc finger protein Metal-binding, Zinc, Zinc-finger3544 7512 ANC_2H01 NM_016332 SEPX1 selenoprotein X, 1 Oxidoreductase,Metal-binding, Zinc, 3545 7513 Selenium, Selenocysteine NM_016333 SRRM2serine/arginine Hypothetical protein 3546 7514 repetitive matrix 2NM_016334 SH120 putative G-protein Receptor 3547 7515 coupled receptorNM_016354 SLC21A12 solute carrier organic Transmembrane, Transport, Ion3548 7516 anion transporter transport, Glycoprotein, Alternative family,member 4A1 splicing NM_016355 LOC51202 DEAD (Asp-Glu-Ala- ATP-binding,Helicase, Hydrolase, 3549 7517 Asp) box polypeptide Hypothetical protein47 NM_016362 GHRL ghrelin precursor Hormone, Cleavage on pair of basic3550 7518 residues, Signal, Lipoprotein, Alternative splicing NM_016364DUSP13 dual specificity Hydrolase 3551 7519 phosphatase 13 NM_016373WWOX WW domain Oxidoreductase 3552 7520 containing oxidoreductaseNM_016377 AKAP7 A kinase (PRKA) Membrane, Myristate, Palmitate, 35537521 anchor protein 7 Lipoprotein, Alternative splicing NM_016381 TREX1three prime repair Exonuclease, Hypothetical protein 3554 7522exonuclease 1 NM_016385 CYLD cylindromatosis Hypothetical protein 35557523 (turban tumor syndrome) NM_016387 HSPC060 hypothetical protein 35567524 HSPC060 NM_016391 HSPC111 hypothetical protein Hypotheticalprotein, Nuclear protein 3557 7525 HSPC111 NM_016397 TH1L TH1-likeTranscription regulation, Repressor, 3558 7526 (Drosophila) Nuclearprotein, Alternative splicing, Alternative initiation NM_016399 HSPC132hypothetical protein Hypothetical protein 3559 7527 HSPC132 NM_016403HSPC148 hypothetical protein Hypothetical protein 3560 7528 HSPC148NM_016407 C20orf43 chromosome 20 Alternative splicing 3561 7529 openreading frame 43 NM_016418 NF2 neurofibromin 2 Structural protein,Cytoskeleton, 3562 7530 (bilateral acoustic Anti-oncogene, Diseasemutation, neuroma) Alternative splicing, Deafness, 3D- structureNM_016424 LUC7A cisplatin resistance- Phosphorylation, Hypothetical 35637531 associated protein overexpressed protein NM_016431 MAPK8IP2mitogen-activated SH3 domain, Alternative splicing 3564 7532 proteinkinase 8 interacting protein 2 NM_016441 CRIM1 cysteine-rich motorSignal 3565 7533 neuron 1 NM_016463 HSPC195 hypothetical proteinHypothetical protein 3566 7534 HSPC195 NM_016465 LOC51238 blocked earlyin Hypothetical protein 3567 7535 transport 1 homolog (S. cerevisiae)like NM_016468 C14orf112 chromosome 14 Hypothetical protein 3568 7536open reading frame 112 NM_016477 FOXP1 forkhead box P1 Hypotheticalprotein, Transcription 3569 7537 regulation, DNA-binding, Zinc-finger,Metal-binding, Nuclear protein, Alternative splicing NM_016479 SCOTINscotin Hypothetical protein 3570 7538 NM_016501 FLJ10597 hypotheticalprotein Hypothetical protein 3571 7539 FLJ10597 NM_016503 MRPL30mitochondrial Hypothetical protein 3572 7540 ribosomal protein L30NM_016507 CRK7 CDC2-related Transferase, Serine/threonine- 3573 7541protein kinase 7 protein kinase, ATP-binding, Nuclear protein NM_016524LOC51760 B/K protein Hypothetical protein 3574 7542 NM_016533 NINJ2ninjurin 2 Cell adhesion, Transmembrane 3575 7543 NM_016538 SIRT7sirtuin (silent mating Hydrolase, NAD, Metal-binding, 3576 7544 typeinformation Zinc, Alternative splicing regulation 2 homolog) 7 (S.cerevisiae) NM_016565 E2IG2 E2IG2 protein 3577 7545 NM_016567 BCCIPBRCA2 and Helicase, Hypothetical protein 3578 7546 CDKN1A interactingprotein NM_016572 USP21 ubiquitin specific Hypothetical protein, Ublconjugation 3579 7547 protease 21 pathway, Hydrolase, Thiol protease,Multigene family NM_016573 LOC51291 Gem-interacting 3580 7548 proteinNM_016574 DRD2 dopamine receptor G-protein coupled receptor, 3581 7549D2 Transmembrane, Glycoprotein, Multigene family, Alternative splicing,Disease mutation, Polymorphism, 3D-structure NM_016582 FLJ20539 solutecarrier family Hypothetical protein 3582 7550 15, member 3 NM_016594FKBP11 FK506 binding Isomerase, Rotamase, Signal 3583 7551 protein 11,19 kDa NM_016598 ZDHHC3 zinc finger, DHHC Transmembrane, Golgi stack,Zinc- 3584 7552 domain containing 3 finger, Alternative splicingNM_016603 C5orf5 chromosome 5 open GTPase activation 3585 7553 readingframe 5 NM_016608 ALEX1 ALEX1 protein Hypothetical protein 3586 7554NM_016610 TLR8 toll-like receptor 8 Hypothetical protein, Receptor, 35877555 Immune response, Inflammatory response, Signal, Transmembrane,Repeat, Leucine-rich repeat, Glycoprotein NM_016612 MSCP mitochondrialsolute Hypothetical protein 3588 7556 carrier protein NM_016616 TXNDC3thioredoxin domain Redox-active center 3589 7557 containing 3(spermatozoa) NM_016619 PLAC8 placenta-specific 8 3590 7558 NM_016623BM-009 hypothetical protein Hypothetical protein 3591 7559 BM-009NM_016626 LOC51320 hypothetical protein Metal-binding, Zinc, Zinc-finger3592 7560 LOC51320 NM_016630 ACP33 acid cluster protein Hypotheticalprotein 3593 7561 33 NM_016639 TNFRSF12A tumor necrosis factor Receptor,Angiogenesis, Apoptosis, 3594 7562 receptor superfamily, Transmembrane,Signal, Alternative member 12A splicing NM_016640 MRPS30 mitochondrialRibosomal protein, Mitochondrion 3595 7563 ribosomal protein S30NM_016733 LIMK2 LIM domain kinase 2 Transferase, Serine/threonine- 35967564 protein kinase, ATP-binding, Repeat, LIM domain, Metal-binding,Zinc, Kinase, Tyrosine-protein kinase, Hypothetical protein NM_016826OGG1 8-oxoguanine DNA Hydrolase, Nuclease, Endonuclease, 3597 7565glycosylase Lyase, DNA repair, Glycosidase, Multifunctional enzyme,Nuclear protein, Mitochondrion, Alternative splicing, Polymorphism, 3D-structure, Transferase, Serine/threonine-protein kinase,Calmodulin-binding, Phosphorylation, NM_016827 OGG1 8-oxoguanine DNAHydrolase, Nuclease, Endonuclease, 3598 7566 glycosylase Lyase, DNArepair, Glycosidase, Multifunctional enzyme, Nuclear protein,Mitochondrion, Alternative splicing, Polymorphism, 3D- structure,Transferase, Serine/threonine-protein kinase, Calmodulin-binding,Phosphorylation, NM_016836 RBMS1 RNA binding motif, DNA-binding, DNAreplication, RNA- 3599 7567 single stranded binding, Nuclear protein,interacting protein 1 Phosphorylation NM_016839 RBMS1 RNA binding motif,DNA-binding, DNA replication, RNA- 3600 7568 single stranded binding,Nuclear protein, interacting protein 1 Phosphorylation NM_016936 UBN1ubinuclein 1 3601 7569 NM_016951 CKLF chemokine-like Chemotaxis,Cytokine, 3602 7570 factor Transmembrane, Alternative splicing NM_017409HOXC10 homeo box C10 Homeobox, DNA-binding, 3603 7571 Developmentalprotein, Nuclear protein, Transcription regulation NM_017414 USP18ubiquitin specific Ubl conjugation pathway, Hydrolase, 3604 7572protease 18 Thiol protease, Multigene family NM_017415 KLHL3 kelch-like3 Cytoskeleton, Actin-binding, Kelch 3605 7573 (Drosophila) repeat,Repeat, Alternative splicing NM_017421 COQ3 coenzyme Q3 Transferase 36067574 homolog, methyltransferase (yeast) NM_017424 CECR1 cat eye syndromeHydrolase, Signal, Hypothetical 3607 7575 chromosome region, proteincandidate 1 NM_017426 NUP54 nucleoporin 54 kDa Hypothetical protein,Transport, 3608 7576 Nuclear protein, Repeat, Glycoprotein, Alternativesplicing NM_017451 BAIAP2 BAI1-associated Receptor, SH3 domain,Hypothetical 3609 7577 protein 2 protein, ATP-binding, TransferaseNM_017455 SDFR1 stromal cell derived Immunoglobulin domain, 3610 7578factor receptor 1 Hypothetical protein, Receptor NM_017456 PSCD1pleckstrin homology, Guanine-nucleotide releasing factor, 3611 7579 Sec7and coiled-coil Coiled coil, Alternative splicing, 3D- domains1(cytohesin structure 1) NM_017491 WDR1 WD repeat domain 1 Repeat, WDrepeat, Hypothetical 3612 7580 protein, Actin-binding, Cytoskeleton,Alternative splicing, Polymorphism NM_017493 HSHIN1 HIV-1 induced 36137581 protein HIN-1 NM_017535 DKFZp566H0824 hypothetical proteinHypothetical protein 3614 7582 DKFZp566H0824 NM_017544 NRF NF-kappa B-Transcription regulation, Repressor, 3615 7583 repressing factorDNA-binding, Nuclear protein NM_017546 C40 hypothetical proteinHypothetical protein 3616 7584 C40 NM_017555 EGLN2 egl nine homolog 2Oxidoreductase, Dioxygenase, 3617 7585 (C. elegans) Nuclear protein,Iron, Vitamin C NM_017567 NAGK N-acetylglucosamine Kinase, Transferase,ATP-binding, 3618 7586 kinase Phosphorylation, Hypothetical proteinNM_017571 LOC55580 hypothetical protein Hypothetical protein 3619 7587LOC55580 NM_017572 MKNK2 MAP kinase- Hypothetical protein, ATP-binding,3620 7588 interacting Kinase, Serine/threonine-protein serine/threoninekinase, Transferase, Translation kinase 2 regulation, Phosphorylation,Alternative splicing NM_017596 KIAA0449 KIAA0449 protein Hypotheticalprotein, Repeat, WD 3621 7589 repeat NM_017622 FLJ20014 hypotheticalprotein Hypothetical protein 3622 7590 FLJ20014 NM_017631 FLJ20035hypothetical protein Hypothetical protein 3623 7591 FLJ20035 NM_017633C6orf37 chromosome 6 open Hypothetical protein 3624 7592 reading frame37 NM_017646 IPT tRNA Hypothetical protein, Transferase 3625 7593isopentenyltransferase 1 NM_017664 ANKRD10 ankyrin repeat Hypotheticalprotein, ANK repeat, 3626 7594 domain 10 Repeat NM_017681 FLJ20130hypothetical protein Hypothetical protein, Porin 3627 7595 FLJ20130NM_017694 FLJ20160 FLJ20160 protein Hypothetical protein 3628 7596NM_017700 FLJ20184 hypothetical protein Hypothetical protein 3629 7597FLJ20184 NM_017703 FBXL12 F-box and leucine- Ubl conjugation pathway,Repeat, 3630 7598 rich repeat protein Leucine-rich repeat, Alternative12 splicing NM_017714 C20orf13 chromosome 20 Hydrolase 3631 7599 openreading frame 13 NM_017730 FLJ20259 FLJ20259 protein Hypotheticalprotein 3632 7600 NM_017735 FLJ20272 hypothetical protein Hypotheticalprotein 3633 7601 FLJ20272 NM_017737 FLJ20275 transducer of Cdc42-Hypothetical protein, SH3 domain 3634 7602 dependent actin assembly 1NM_017740 ZDHHC7 zinc finger, DHHC Transmembrane, Zinc-finger, 3635 7603domain containing 7 Alternative splicing NM_017742 FLJ20281 zinc finger,CCHC Hypothetical protein, Zinc-finger 3636 7604 domain containing 2NM_017746 FLJ20287 hypothetical protein Hypothetical protein 3637 7605FLJ20287 NM_017756 FLJ20306 hypothetical protein Hypothetical protein3638 7606 FLJ20306 NM_017775 FLJ20343 hypothetical protein Hypotheticalprotein 3639 7607 FLJ20343 NM_017785 FLJ20364 hypothetical proteinHypothetical protein 3640 7608 FLJ20364 NM_017787 FLJ20154 chromosome 10Hypothetical protein 3641 7609 open reading frame 26 NM_017801 CKLFSF6chemokine-like Chemotaxis, Cytokine, 3642 7610 factor super family 6Transmembrane NM_017803 FLJ20399 hypothetical protein Hypotheticalprotein 3643 7611 FLJ20399 NM_017812 FLJ20420 hypothetical proteinHypothetical protein 3644 7612 FLJ20420 NM_017814 FLJ20422 hypotheticalprotein Hypothetical protein 3645 7613 FLJ20422 NM_017816 LYARhypothetical protein Hypothetical protein 3646 7614 FLJ20425 NM_017817RAB20 RAB20, member GTP-binding, Lipoprotein, 3647 7615 RAS oncogenePrenylation, Protein transport, family Polymorphism NM_017819 FLJ20432hypothetical protein Hypothetical protein 3648 7616 FLJ20432 NM_017820FLJ20433 hypothetical protein Hypothetical protein 3649 7617 FLJ20433NM_017821 RHBDL2 rhomboid, veinlet- Hydrolase, Protease, Serine 36507618 like 2 (Drosophila) protease, Transmembrane NM_017824 FLJ20445hypothetical protein Hypothetical protein 3651 7619 FLJ20445 NM_017836FLJ20473 hypothetical protein Hypothetical protein 3652 7620 FLJ20473NM_017838 NOLA2 nucleolar protein 3653 7621 family A, member 2 (H/ACAsmall nucleolar RNPs) NM_017840 MRPL16 mitochondrial Ribosomal protein,Hypothetical 3654 7622 ribosomal protein protein L16 NM_017844 ANKMY1ankyrin repeat and Hypothetical protein, ANK repeat, 3655 7623 MYNDdomain Repeat, Zinc-finger, Alternative containing 1 splicing NM_017847C1orf27 chromosome 1 open Hypothetical protein 3656 7624 reading frame27 NM_017849 FLJ20507 hypothetical protein Hypothetical protein 36577625 FLJ20507 NM_017850 FLJ20508 hypothetical protein Hypotheticalprotein 3658 7626 FLJ20508 NM_017859 URKL1 uridine kinase-like 1Transferase, Kinase, ATP-binding 3659 7627 NM_017866 FLJ20533hypothetical protein Hypothetical protein 3660 7628 FLJ20533 NM_017874C20orf27 chromosome 20 Hypothetical protein 3661 7629 open reading frame27 NM_017885 FLJ20568 host cell factor C1 Hypothetical protein 3662 7630regulator 1 (XPO1 dependant) NM_017895 DDX27 DEAD (Asp-Glu-Ala-Hydrolase, Helicase, ATP-binding, 3663 7631 Asp) box polypeptide Nuclearprotein, Alternative splicing 27 NM_017899 TSC hypothetical proteinCalcium-binding, Hypothetical 3664 7632 FLJ20607 protein NM_017900FLJ20608 aurora-A kinase Hypothetical protein, Nuclear protein 3665 7633interacting protein NM_017906 FLJ20624 PAK1 interacting Hypotheticalprotein, Repeat, WD 3666 7634 protein 1 repeat NM_017907 FLJ20625hypothetical protein Hypothetical protein 3667 7635 FLJ20625 NM_017910FLJ20628 hypothetical protein Hypothetical protein 3668 7636 FLJ20628NM_017942 BTBD1 BTB (POZ) domain 3669 7637 containing 1 NM_017952FLJ20758 FLJ20758 protein Hypothetical protein 3670 7638 NM_017953FLJ20729 hypothetical protein Hypothetical protein 3671 7639 FLJ20729NM_017956 FLJ20772 hypothetical protein Hypothetical protein 3672 7640FLJ20772 NM_017983 KIAA1001 hypothetical protein Hypothetical protein,Repeat, WD 3673 7641 FLJ10055 repeat NM_018007 FBXO4 Homo sapiens cDNAUbl conjugation pathway, 3674 7642 FLJ10141 fis, clone Hypotheticalprotein HEMBA1003199. NM_018024 FLJ10204 hypothetical proteinHypothetical protein 3675 7643 FLJ10204 NM_018044 WBSCR20A WilliamsBeuren Nuclear protein, Transport, 3676 7644 syndrome Transmembrane,Repeat, chromosome region Hypothetical protein 20A NM_018045 FLJ10276hypothetical protein Hypothetical protein 3677 7645 FLJ10276 NM_018050FLJ10298 hypothetical protein Hypothetical protein 3678 7646 FLJ10298NM_018051 FLJ10300 hypothetical protein Hypothetical protein, Repeat, WD3679 7647 FLJ10300 repeat NM_018053 FLJ10307 hypothetical proteinHypothetical protein 3680 7648 FLJ10307 NM_018056 FLJ10315 hypotheticalprotein Hypothetical protein 3681 7649 FLJ10315 NM_018059 FLJ10324hypothetical protein Hypothetical protein 3682 7650 FLJ10324 NM_018067FLJ10350 hypothetical protein Hypothetical protein 3683 7651 FLJ10350NM_018075 FLJ10375 hypothetical protein Hypothetical protein 3684 7652FLJ10375 NM_018087 FLJ10407 hypothetical protein Hypothetical protein3685 7653 FLJ10407 NM_018089 FLJ10415 hypothetical protein Hypotheticalprotein, ANK repeat, 3686 7654 FLJ10415 Repeat NM_018093 FLJ10439hypothetical protein Hypothetical protein, Repeat, WD 3687 7655 FLJ10439repeat NM_018099 FLJ10462 hypothetical protein Hypothetical protein 36887656 FLJ10462 NM_018100 FLJ10466 EF-hand domain (C- Hypothetical protein3689 7657 terminal) containing 1 NM_018113 LIMR lipocalin-interactingHypothetical protein, Receptor 3690 7658 membrane receptor NM_018119 SINRNA polymerase III Transferase, DNA-directed RNA 3691 7659 80 kDasubunit polymerase, Transcription, Nuclear RPC5 protein, Alternativesplicing NM_018125 FLJ10521 hypothetical protein Hypothetical protein3692 7660 FLJ10521 NM_018127 ELAC2 elaC homolog 2 (E. coli) Hypotheticalprotein 3693 7661 NM_018128 SRR hypothetical protein Isomerase,Pyridoxal phosphate, 3694 7662 FLJ10534 Hypothetical protein NM_018137PRMT6 protein arginine N- Transferase, Methyltransferase, 3695 7663methyltransferase 6 Nuclear protein, Methylation NM_018140 FLJ10565hypothetical protein Hypothetical protein 3696 7664 FLJ10565 NM_018142FLJ10569 hypothetical protein Hypothetical protein 3697 7665 FLJ10569NM_018147 FAIM Fas apoptotic Apoptosis, Alternative splicing 3698 7666inhibitory molecule NM_018158 SLC4A1AP solute carrier familyHypothetical protein, Transcription 3699 7667 4 (anion exchanger),regulation, Nuclear protein, Antigen, member 1, adaptor Alternativesplicing protein NM_018161 FLJ10631 NAD synthetase 1 Hypotheticalprotein 3700 7668 NM_018169 FLJ10652 hypothetical protein Hypotheticalprotein 3701 7669 FLJ10652 NM_018170 FLJ10656 hypothetical proteinKinase, Hypothetical protein 3702 7670 FLJ10656 NM_018174 VCY2IP1 VCY2interacting Hypothetical protein 3703 7671 protein 1 NM_018182 FLJ10700hypothetical protein Hypothetical protein 3704 7672 FLJ10700 NM_018191RCBTB1 regulator of Hypothetical protein 3705 7673 chromosomecondensation (RCC1) and BTB (POZ) domain containing protein 1 NM_018194FLJ10724 melanoma antigen Hypothetical protein 3706 7674 recognized by Tcells 2 NM_018195 FLJ10726 hypothetical protein Hypothetical protein3707 7675 FLJ10726 NM_018197 ZFP64 zinc finger protein 64 Transcriptionregulation, Zinc-finger, 3708 7676 homolog (mouse) Metal-binding,Nuclear protein, DNA- binding, Repeat, Alternative splicing NM_018203FLJ10748 hypothetical protein Hypothetical protein 3709 7677 FLJ10748NM_018208 FLJ10761 putative Transferase, Kinase 3710 7678 ethanolaminekinase NM_018209 ARFGAP1 ADP-ribosylation Transport, Protein transport,3711 7679 factor GTPase GTPase activation, Golgi stack, activatingprotein 1 Zinc-finger, Alternative splicing, Polymorphism NM_018217C20orf31 chromosome 20 Hydrolase, Glycosidase, 3712 7680 open readingframe Glycoprotein, Signal, Polymorphism 31 NM_018226 RNPEPL1 arginylAminopeptidase, Hydrolase, Zinc, 3713 7681 aminopeptidaseMetalloprotease (aminopeptidase B)- like 1 NM_018235 FLJ10830 cytosolicnonspecific Hydrolase, Carboxypeptidase, 3714 7682 dipeptidase (ECMetalloprotease, Hypothetical 3.4.13.18) protein NM_018243 FLJ10849hypothetical protein Hypothetical protein 3715 7683 FLJ10849 NM_018246FLJ10853 hypothetical protein Hypothetical protein 3716 7684 FLJ10853NM_018255 STATIP1 signal transducer Hypothetical protein, Repeat, WD3717 7685 and activator of repeat transcription 3 interacting protein 1NM_018256 WDR12 WD repeat domain Repeat, WD repeat, Polymorphism 37187686 12 NM_018257 C20orf36 chromosome 20 Transcription regulation,Zinc-finger, 3719 7687 open reading frame DNA-binding, Nuclear protein,36 Repeat, Alternative splicing NM_018259 FLJ10890 hypothetical proteinHypothetical protein 3720 7688 FLJ10890 NM_018264 FLJ10900 hypotheticalprotein Hypothetical protein 3721 7689 FLJ10900 NM_018265 FLJ10901hypothetical protein Hypothetical protein 3722 7690 FLJ10901 NM_018267H2AFJ H2A histone family, Hypothetical protein 3723 7691 member JNM_018275 FLJ10925 hypothetical protein Hypothetical protein 3724 7692FLJ10925 NM_018306 FLJ11036 hypothetical protein Hypothetical protein3725 7693 FLJ11036 NM_018317 FLJ11082 hypothetical protein Hypotheticalprotein 3726 7694 FLJ11082 NM_018319 TDP1 tyrosyl-DNA Hypotheticalprotein, Hydrolase, 3727 7695 phosphodiesterase 1 DNA repair, Repeat,Nuclear protein, 3D-structure, Disease mutation NM_018321 RAD1 BRIXHypothetical protein, Ribosome 3728 7696 biogenesis, Nuclear protein,Cell cycle, Exonuclease NM_018322 C6orf64 chromosome 6 open Hypotheticalprotein, Dynein 3729 7697 reading frame 64 NM_018324 FLJ11106hypothetical protein Hypothetical protein 3730 7698 FLJ11106 NM_018326HIMAP4 immunity associated GTP-binding, Coiled coil, 3731 7699 protein 4Polymorphism NM_018332 DDX19 hypothetical protein ATP-binding, Helicase,Hydrolase, 3732 7700 FLJ11126 RNA-binding, Nuclear protein, Hypotheticalprotein NM_018333 FLJ20666 hypothetical protein Hypothetical protein3733 7701 FLJ20666 NM_018358 FLJ11198 ATP-binding Hypothetical protein,ATP-binding 3734 7702 cassette, sub-family F (GCN20), member 3 NM_018359FLJ11200 hypothetical protein Hypothetical protein 3735 7703 FLJ11200NM_018361 FLJ11210 acid acyltransferase- Phospholipid biosynthesis, 37367704 epsilon Transferase, Acyltransferase, Transmembrane NM_018371 ChGnchondroitin beta1,4 Transferase, Hypothetical protein 3737 7705 N-acetylgalactosaminyl transferase NM_018373 SYNJ2BP synaptojanin 2Mitochondrion, Outer membrane, 3738 7706 binding protein TransmembraneNM_018379 FLJ11280 hypothetical protein Hypothetical protein 3739 7707FLJ11280 NM_018386 FLJ11305 hypothetical protein Hypothetical protein3740 7708 FLJ11305 NM_018387 STRBP spermatid Hypothetical protein 37417709 perinuclear RNA binding protein NM_018391 FLJ23277 ubiquitinspecific Hypothetical protein, Protease 3742 7710 protease 31 NM_018394FLJ11342 hypothetical protein Hypothetical protein 3743 7711 FLJ11342NM_018399 VNN3 vanin 3 Hydrolase, Signal, Glycoprotein, 3744 7712GPI-anchor, Lipoprotein NM_018403 HSA275986 transcription factorHypothetical protein 3745 7713 SMIF NM_018404 CENTA2 centaurin, alpha 2GTPase activation, Repeat, Zinc- 3746 7714 finger NM_018407 LAPTM4Blysosomal 3747 7715 associated protein transmembrane 4 beta NM_018421TBC1D2 TBC1 domain family, Hypothetical protein, GTPase 3748 7716 member2 activation, Antigen NM_018422 DKFZp761K1423 hypothetical proteinHypothetical protein 3749 7717 DKFZp761K1423 NM_018423 DKFZp761p1010protein kinase ATP-binding, Kinase, Receptor, 3750 7718 STYK1Transferase, Tyrosine-protein kinase, Hypothetical protein NM_018441PECR peroxisomal trans 2- Oxidoreductase 3751 7719 enoyl CoA reductaseNM_018443 ZNF302 zinc finger protein Hypothetical protein,Metal-binding, 3752 7720 302 Zinc, Zinc-finger, Transcriptionregulation, DNA-binding, Nuclear protein, Repeat, Alternative splicingNM_018449 UBAP2 ubiquitin associated Hypothetical protein 3753 7721protein 2 NM_018452 C6orf35 chromosome 6 open Hypothetical protein 37547722 reading frame 35 NM_018457 DKFZP564J157 DKFZp564J157 Hypotheticalprotein 3755 7723 protein NM_018465 MDS030 chromosome 9 openHypothetical protein 3756 7724 reading frame 46 NM_018472 HT011uncharacterized Hypothetical protein 3757 7725 hypothalamus proteinHT011 NM_018480 HT007 uncharacterized Hypothetical protein 3758 7726hypothalamus protein HT007 NM_018485 GPR77 G protein-coupled G-proteincoupled receptor, 3759 7727 receptor 77 Transmembrane, GlycoproteinNM_018486 HDAC8 histone deacetylase 8 Hydrolase, Nuclear protein, 37607728 Chromatin regulator, Transcription regulation, Repressor,Alternative splicing NM_018491 LOC55871 COBW-like protein Hypotheticalprotein 3761 7729 NM_018515 PRO2176 EST, Highly similar 3762 7730 tohypothetical protein PRO2176 [Homo sapiens] [H. sapiens] NM_018520PRO2268 hypothetical protein 3763 7731 PRO2268 NM_018533 RAB7 Homosapiens cDNA GTP-binding, Lipoprotein, 3764 7732 FLJ20819 fis, clonePrenylation, Protein transport, ADSE00511. Hypothetical proteinNM_018556 SIRPB2 signal-regulatory Repeat, Signal, Transmembrane, 37657733 protein beta 2 Immunoglobulin domain, Glycoprotein, Alternativesplicing NM_018569 PRO0971 hypothetical protein Hypothetical protein3766 7734 PRO0971 NM_018572 PRO1051 E2F transcription 3767 7735 factor 3NM_018590 PRO0082 chondroitin sulfate Hypothetical protein, Transferase3768 7736 GalNAcT-2 NM_018594 PRO0823 FYN binding protein SH3 domain,Phosphorylation, 3769 7737 (FYB-120/130) Nuclear protein, Coiled coil,Alternative splicing NM_018615 PRO2032 Homo sapiens 3770 7738hypothetical protein PRO2032 (PRO2032), mRNA. NM_018638 EKI1ethanolamine kinase Transferase, Kinase 3771 7739 NM_018643 TREM1triggering receptor Receptor 3772 7740 expressed on myeloid cells 1NM_018648 NOLA3 nucleolar protein 3773 7741 family A, member 3 (H/ACAsmall nucleolar RNPs) NM_018676 THSD1 thrombospondin, Signal 3774 7742type I, domain 1 NM_018687 LOC55908 hepatocellular 3775 7743 carcinoma-associated gene TD26 NM_018688 BIN3 bridging integrator 3 Septation,Cytoskeleton, Coiled coil, 3776 7744 Hypothetical protein NM_018690APOB48R apolipoprotein B48 Hypothetical protein, Lipoprotein, 3777 7745receptor Receptor NM_018699 PRDM5 PR domain Transcription regulation,DNA- 3778 7746 containing 5 binding, Zinc-finger, Metal-binding, Nuclearprotein, Repeat NM_018728 MYO5C myosin VC Myosin, Repeat, ATP-binding,3779 7747 Calmodulin-binding, Actin-binding, Coiled coil, PolymorphismNM_018834 MATR3 matrin 3 Nuclear protein, RNA-binding, 3780 7748 Repeat,Zinc-finger NM_018839 NSFL1C NSFL1 (p97) Hypothetical protein 3781 7749cofactor (p47) NM_018840 C20orf24 chromosome 20 Alternative splicing,Membrane, SH2 3782 7750 open reading frame domain, SH3 domain,Myristate, 24 Phosphorylation, Alternative initiation, LipoproteinNM_018939 PCDHB6 protocadherin beta 6 Calcium-binding, Cell adhesion,3783 7751 Glycoprotein, Signal, Repeat, Transmembrane, Multigene familyNM_018959 DAZAP1 DAZ associated Hypothetical protein 3784 7752 protein 1NM_018961 UBASH3A ubiquitin associated Nuclear protein, SH3 domain, 37857753 and SH3 domain Alternative splicing containing, A NM_018983 NOLA1nucleolar protein 3786 7754 family A, member 1 (H/ACA small nucleolarRNPs) NM_018996 FLJ20015 KIAA1582 protein Hypothetical protein 3787 7755NM_019002 ETAA16 ETAA16 protein 3788 7756 NM_019009 TOLLIP tollinteracting Hypothetical protein, Immune 3789 7757 protein response,Inflammatory response NM_019012 PEPP2 phosphoinositol 3- Hypotheticalprotein 3790 7758 phosphate-binding protein-2 NM_019018 FLJ11127hypothetical protein Hypothetical protein 3791 7759 FLJ11127 NM_019042FLJ20485 hypothetical protein Hypothetical protein, tRNA 3792 7760FLJ20485 processing, Lyase NM_019057 FLJ10404 hypothetical proteinHypothetical protein 3793 7761 FLJ10404 NM_019063 EML4 echinodermMicrotubule, Repeat, WD repeat, 3794 7762 microtubule Hypotheticalprotein associated protein like 4 NM_019067 FLJ10613 hypotheticalprotein Hypothetical protein 3795 7763 FLJ10613 NM_019084 FLJ10895hypothetical protein Hypothetical protein 3796 7764 FLJ10895 NM_019096GTPBP2 GTP binding protein 2 GTP-binding, Protein biosynthesis, 37977765 Hypothetical protein NM_019112 ABCA7 ATP-binding ATP-binding,Hypothetical protein 3798 7766 cassette, sub-family A (ABC1), member 7NM_019554 S100A4 S100 calcium Calcium-binding, 3D-structure 3799 7767binding protein A4 (calcium protein, calvasculin, metastasin, murineplacental homolog) NM_019604 CRTAM class-I MHC- 3800 7768 restricted Tcell associated molecule NM_019848 P3 solute carrier familyTransmembrane, Transport, 3801 7769 10 (sodium/bile acid Symportcotransporter family), member 3 NM_019892 PPI5PIV inositol 3802 7770polyphosphate-5- phosphatase, 72 kDa NM_019896 POLE4 polymerase (DNA-DNA-directed DNA polymerase, 3803 7771 directed), epsilon 4 DNA-binding,Nuclear protein (p12 subunit) NM_020038 ABCC3 ATP-binding ATP-binding,Glycoprotein, 3804 7772 cassette, sub-family Transmembrane, Transport,Repeat, C (CFTR/MRP), Alternative splicing member 3 NM_020123 SMBPSM-11044 binding Hypothetical protein, Signal, 3805 7773 proteinTransmembrane NM_020133 LPAAT- 1-acylglycerol-3- Phospholipidbiosynthesis, 3806 7774 delta phosphate O- Transferase, Acyltransferase,acyltransferase 4 Transmembrane (lysophosphatidic acid acyltransferase,delta) NM_020134 DPYSL5 dihydropyrimidinase- Hypothetical protein 38077775 like 5 NM_020135 WHIP Werner helicase ATP-binding, Helicase,Hypothetical 3808 7776 interacting protein 1 protein NM_020139 LOC56898dehydrogenase/reductase Oxidoreductase, Hypothetical protein 3809 7777(SDR family) member 6 NM_020143 LOC56902 putatative 28 kDa Hypotheticalprotein 3810 7778 protein NM_020149 MEIS2 Meis1, myeloid Hypotheticalprotein, Homeobox, 3811 7779 ecotropic viral DNA-binding, Nuclearprotein, integration site 1 Alternative splicing homolog 2 (mouse)NM_020152 C21orf7 chromosome 21 Alternative splicing, Hypothetical 38127780 open reading frame 7 protein NM_020158 RRP46 exosome componentExosome, Hydrolase, Nuclease, 3813 7781 Rrp46 Exonuclease, rRNAprocessing, Nuclear protein, RNA-binding, Antigen NM_020166 MCCC1methylcrotonoyl- Mitochondrion, Ligase, Biotin, ATP- 3814 7782 CoenzymeA binding, Transit peptide, Disease carboxylase 1 mutation, Polymorphism(alpha) NM_020179 FN5 FN5 protein 3815 7783 NM_020184 CNNM4 cyclin M4Hypothetical protein 3816 7784 NM_020188 DC13 DC13 protein 3817 7785NM_020193 C11ORF30 chromosome 11 Hypothetical protein 3818 7786 openreading frame 30 NM_020198 GK001 GK001 protein Hypothetical protein 38197787 NM_020200 HHGP phosphoribosyl Transferase 3820 7788 transferasedomain containing 1 NM_020201 NT5M 5′,3′-nucleotidase, Nucleotidemetabolism, Hydrolase, 3821 7789 mitochondrial Mitochondrion,Nucleotide-binding, Magnesium, Transit peptide, 3D- structure NM_020216RNPEP arginyl Aminopeptidase, Hydrolase, Zinc, 3822 7790 aminopeptidaseMetalloprotease (aminopeptidase B) NM_020229 PRDM11 PR domainHypothetical protein 3823 7791 containing 11 NM_020231 MDS010 x 010protein Hypothetical protein 3824 7792 NM_020234 MDS009 x 009 proteinHypothetical protein 3825 7793 NM_020236 MRPL1 mitochondrialHypothetical protein, Ribosomal 3826 7794 ribosomal protein L1 proteinNM_020239 SPEC1 small protein effector Hypothetical protein 3827 7795 1of Cdc42 NM_020243 TOMM22 translocase of outer Receptor, Translocation,Transport, 3828 7796 mitochondrial Protein transport, Outer membrane,membrane 22 Mitochondrion, Transmembrane homolog (yeast) NM_020313LOC57019 hypothetical protein Hypothetical protein 3829 7797 LOC57019NM_020314 MGC16824 esophageal cancer Hypothetical protein 3830 7798associated protein NM_020322 ACCN3 amiloride-sensitive Ionic channel3831 7799 cation channel 3 NM_020344 SLC24A2 solute carrier familyVision, Transport, Antiport, Symport, 3832 7800 24 Calcium transport,Potassium (sodium/potassium/calcium transport, Sodium transport,exchanger), Transmembrane, Glycoprotein, member 2 Signal, Repeat,Alternative splicing NM_020347 LZTFL1 leucine zipper 3833 7801transcription factor- like 1 NM_020350 AGTRAP angiotensin II Receptor3834 7802 receptor-associated protein NM_020357 PCNP PEST-containingNuclear protein 3835 7803 nuclear protein NM_020360 PLSCR3 phospholipidHypothetical protein, 3836 7804 scramblase 3 Transmembrane, Lipoprotein,Calcium-binding, SH3-binding, Repeat, Phosphorylation, Palmitate,Polymorphism NM_020365 EIF2B3 eukaryotic Initiation factor, Proteinbiosynthesis, 3837 7805 translation initiation Alternative splicing,Disease factor 2B, subunit 3 mutation, Hypothetical protein gamma, 58kDa NM_020366 RPGRIP1 retinitis pigmentosa 3838 7806 GTPase regulatorinteracting protein 1 NM_020370 GPR84 G protein-coupled Receptor 38397807 receptor 84 NM_020371 AVEN apoptosis, caspase Apoptosis 3840 7808activation inhibitor NM_020385 XPMC2H XPMC2 prevents Hypotheticalprotein 3841 7809 mitotic catastrophe 2 homolog (Xenopus laevis)NM_020390 EIF5A2 eukaryotic Initiation factor, Hypothetical protein 38427810 translation initiation factor 5A2 NM_020394 LOC57116 zinc fingerprotein Metal-binding, Zinc, Zinc-finger 3843 7811 SBZF3 NM_020399 PISTgolgi associated Hypothetical protein 3844 7812 PDZ and coiled-coilmotif containing NM_020401 NUP107 nuclear pore Nuclear protein,Transport 3845 7813 complex protein NM_020406 PRV1 polycythemia rubraSignal, Receptor 3846 7814 vera 1 NM_020408 CGI-203 chromosome 6 openHypothetical protein 3847 7815 reading frame 149 NM_020410 CGI-152cation-transporting Hydrolase, Transmembrane, 3848 7816 ATPasePhosphorylation, Magnesium, ATP- binding, Alternative splicing,Hypothetical protein NM_020414 DDX24 DEAD (Asp-Glu-Ala- Hydrolase,Helicase, ATP-binding, 3849 7817 Asp) box polypeptide RNA-binding 24NM_020415 RETN resistin Hormone, Signal, Diabetes mellitus, 3850 7818Obesity NM_020466 DJ122O8.2 hypothetical protein Hypothetical protein3851 7819 dJ122O8.2 NM_020469 ABO ABO blood group Transferase,Glycosyltransferase, 3852 7820 (transferase A, alpha Blood groupantigen, Golgi stack, 1-3-N- Metal-binding, Manganese, Signal-acetylgalactosaminyl anchor, Transmembrane, transferase; Glycoprotein,Polymorphism, 3D- transferase B, alpha structure 1-3-galactosyltransferase) NM_020480 ANK1 ankyrin 1, ANK repeat, Repeat,Cytoskeleton, 3853 7821 erythrocytic Alternative splicing,Phosphorylation, Lipoprotein, Disease mutation, Elliptocytosis,Polymorphism NM_020484 AF011757 Homo sapiens 3854 7822 RAGE bindingprotein (AF011757), mRNA. NM_020530 OSM oncostatin M Growth regulation,Cytokine, 3855 7823 Glycoprotein, Signal, 3D-structure NM_020533 MCOLN1mucolipin 1 Hypothetical protein, Ionic channel, 3856 7824 TransmembraneNM_020548 DBI diazepam binding Transport, Lipid-binding, Acetylation,3857 7825 inhibitor (GABA Alternative splicing receptor modulator,acyl-Coenzyme A binding protein) NM_020632 ATP6V0A4 ATPase, H+ Hydrogenion transport, 3858 7826 transporting, Transmembrane, Glycoprotein,lysosomal V0 Disease mutation, Hypothetical subunit a isoform 4 proteinNM_020639 ANKRD3 ankyrin repeat ANK repeat, Repeat, Hypothetical 38597827 domain 3 protein, ATP-binding, Kinase, Serine/threonine-proteinkinase, Transferase, Alternative splicing NM_020648 TWSG1 twistedgastrulation Hypothetical protein, Signal 3860 7828 homolog 1(Drosophila) NM_020652 ZNF286 zinc finger protein Transcriptionregulation, Zinc-finger, 3861 7829 286 Metal-binding, Nuclear protein,DNA- binding, Repeat NM_020659 TTYH1 tweety homolog 1 3862 7830(Drosophila) NM_020664 DECR2 2,4-dienoyl CoA Hypothetical protein,Oxidoreductase 3863 7831 reductase 2, peroxisomal NM_020686 NPD0094-aminobutyrate 3864 7832 aminotransferase NM_020905 RDH14 retinolOxidoreductase, NADP 3865 7833 dehydrogenase 14 (all-trans and 9-cis)NM_020980 AQP9 aquaporin 9 Transport, Repeat, Transmembrane 3866 7834NM_020983 ADCY6 adenylate cyclase 6 Lyase, cAMP biosynthesis, 3867 7835Transmembrane, Glycoprotein, Repeat, Metal-binding, Magnesium,Alternative splicing NM_020995 HPR haptoglobin-related Hydrolase,Protease, Serine 3868 7836 protein protease NM_020999 NEUROG3 neurogenin3 3869 7837 NM_021018 HIST1H3F histone 1, H3f Nuclear protein,Chromosomal 3870 7838 protein, DNA-binding, Nucleosome core, Multigenefamily, Acetylation, Methylation NM_021019 MYL6 myosin, light Myosin,Muscle protein, Acetylation, 3871 7839 polypeptide 6, alkali,Alternative splicing, Multigene family smooth muscle and non-muscleNM_021025 TLX3 T-cell leukemia, Homeobox, DNA-binding, Nuclear 3872 7840homeobox 3 protein, Developmental protein NM_021031 CYCL Homo sapiensHypothetical protein 3873 7841 cytochrome c-like antigen (CYCL), mRNANM_021039 S100A14 S100 calcium Transcription regulation, DNA- 3874 7842binding protein A14 binding, Nuclear protein, (calgizzarin) Hypotheticalprotein, Calcium- binding NM_021074 NDUFV2 NADH Oxidoreductase, NAD,Ubiquinone, 3875 7843 dehydrogenase Mitochondrion, Transit peptide,(ubiquinone) Metal-binding, Iron-sulfur, Iron, 2Fe—2S, flavoprotein 2,Polymorphism 24 kDa NM_021075 NDUFV3 NADH Hypothetical protein 3876 7844dehydrogenase (ubiquinone) flavoprotein 3, 10 kDa NM_021078 GCN5L2 GCN5general Transcription regulation, 3877 7845 control of amino-acidTransferase, Nuclear protein, synthesis 5-like 2 Bromodomain,Alternative splicing, (yeast) 3D-structure NM_021079 NMT1 N-Acyltransferase, Transferase, 3878 7846 myristoyltransferase 1Alternative splicing NM_021090 MTMR3 myotubularin related Hydrolase,Zinc-finger, Alternative 3879 7847 protein 3 splicing NM_021103 TMSB10thymosin, beta 10 Actin-binding, Cytoskeleton, 3880 7848 AcetylationNM_021106 RGS3 regulator of G- Hypothetical protein, Signal 3881 7849protein signalling 3 transduction inhibitor, Alternative splicing,Phosphorylation NM_021131 PPP2R4 protein phosphatase Alternativesplicing 3882 7850 2A, regulatory subunit B′ (PR 53) NM_021173 POLD4polymerase (DNA- DNA-directed DNA polymerase, 3883 7851 directed), delta4 DNA replication, Nuclear protein NM_021178 HEI10 chromosome 14 Ublconjugation pathway, Ligase, 3884 7852 open reading frame Nuclearprotein, Metal-binding, Zinc, 18 Coiled coil, Zinc-finger,Phosphorylation, Ubl conjugation NM_021197 WFDC1 WAP four-disulfideSerine protease inhibitor, Signal 3885 7853 core domain 1 NM_021198NLI-IF CTD (carboxy- Hypothetical protein, Nuclear protein 3886 7854terminal domain, RNA polymerase II, polypeptide A) small phosphatase 1NM_021199 SQRDL sulfide quinone Oxidoreductase, Flavoprotein, FAD, 38877855 reductase-like NADP, Mitochondrion, Transit (yeast) peptide,Polymorphism NM_021212 ZF HCF-binding DNA-binding, Nuclear protein 38887856 transcription factor Zhangfei NM_021238 TERA TERA proteinHypothetical protein 3889 7857 NM_021242 STRAIT11499 MID1 interactingHypothetical protein 3890 7858 G12-like protein NM_021251 CAPN10 calpain10 Hydrolase, Thiol protease, Repeat, 3891 7859 Alternative splicing,Polymorphism, Diabetes mellitus NM_021259 TMEM8 transmembrane Celladhesion, Signal, 3892 7860 protein 8 (five Transmembrane, EGF-likedomain, membrane-spanning Glycoprotein domains) S73288 small smallproline-rich 3893 7861 proline-rich protein 1A protein SPRK S74639 IGHMClone I50 Immunoglobulin domain, 3894 7862 immunoglobulin ImmunoglobulinC region, heavy chain variable Glycoprotein, Repeat, Pyrrolidone regionmRNA, partial carboxylic acid, Polymorphism, cds Membrane, Hypotheticalprotein, Receptor, T-cell, Signal S77356 ATP5O ATP synthase, H+Hydrolase, ATP synthesis, CF(1), 3895 7863 transporting, Hydrogen iontransport, mitochondrial F1 Mitochondrion, Transit peptide, complex, Osubunit Polymorphism (oligomycin sensitivity conferring protein) S80864cytochrome cytochrome c-like Hypothetical protein 3896 7864 c-likeantigen polypeptide S90469 POR P450 (cytochrome) Oxidoreductase,Flavoprotein, FMN, 3897 7865 oxidoreductase FAD, NADP, Endoplasmicreticulum, Membrane, Acetylation, Polymorphism, 3D-structure U00946KIAA0344 protein kinase, lysine Hypothetical protein, ATP-binding, 38987866 deficient 1 Kinase, Serine/threonine-protein kinase, TransferaseU01147 ABR active BCR-related Guanine-nucleotide releasing factor, 38997867 gene Alternative splicing U02032 RPL23A ribosomal protein Ribosomalprotein, rRNA-binding 3900 7868 L23a U09196 POLD4 polymerase (DNA-DNA-directed DNA polymerase, 3901 7869 directed), delta 4 DNAreplication, Nuclear protein U14383 MUC8 Human mucin 3902 7870 (MUC8)mRNA, partial cds. U20180 IREB2 iron-responsive Iron-sulfur, 4Fe—4S,RNA-binding, 3903 7871 element binding Hypothetical protein protein 2U25750 hypothetical protein Hypothetical protein 3904 7872 MGC20235U36759 PTCRA pre T-cell antigen 3905 7873 receptor alpha U37689 POLR2Hpolymerase (RNA) II Transferase, DNA-directed RNA 3906 7874 (DNAdirected) polymerase, Transcription, Nuclear polypeptide H proteinU41387 DDX21 DEAD (Asp-Glu-Ala- Helicase, RNA-binding, ATP-binding, 39077875 Asp) box polypeptide Nuclear protein, Antigen, Repeat 21 U43431TOP3A topoisomerase Isomerase, Topoisomerase, DNA- 3908 7876 (DNA) IIIalpha binding, Repeat, Zinc-finger, Alternative splicing, PolymorphismU43604 Human unidentified 3909 7877 mRNA, partial sequence. U56725 HSPA2Human heat shock ATP-binding, Chaperone, Heat 3910 7878 protein mRNA,shock, Multigene family complete cds. U58033 MTMR2 myotubularin relatedHydrolase, Charcot-Marie-Tooth 3911 7879 protein 2 disease U64205 MARK3MAP/microtubule Transferase, Serine/threonine- 3912 7880affinity-regulating protein kinase, ATP-binding, kinase 3 Alternativesplicing, Plasmid U66702 PTPRN2 protein tyrosine Hypothetical protein,Hydrolase, 3913 7881 phosphatase, Receptor, Glycoprotein, Signal,receptor type, N Transmembrane, Diabetes mellitus, polypeptide 2Alternative splicing U68382 MAN2B1 mannosidase, alpha, Glycosidase,Hydrolase, 3914 7882 class 2B, member 1 Glycoprotein, Lysosome, Zymogen,Signal, Disease mutation, Polymorphism U68494 solute carrier family 39157883 30 (zinc transporter), member 1 U69127 FUBP3 far upstreamTranscription regulation, Transacting 3916 7884 element (FUSE) factor,Nuclear protein, DNA- binding protein 3 binding, Repeat, Alternativesplicing U69645 ZNF32 zinc finger protein 32 Hypothetical protein,Metal-binding, 3917 7885 (KOX 30) Zinc, Zinc-finger, Transcriptionregulation, DNA-binding, Nuclear protein, Repeat U72882 IFI35interferon-induced Interferon induction, Alternative 3918 7886 protein35 splicing U79246 DIS3 FLJ22624 protein Hypothetical protein 3919 7887U79260 MGC5149 fatso Hypothetical protein 3920 7888 U79277 tyrosine 3-Neurone, Phosphorylation, 3921 7889 monooxygenase/tryptophanAcetylation, Multigene family, 3D- 5- structure monooxygenase activationprotein, zeta polypeptide U79280 PIPPIN RNA-binding protein Hypotheticalprotein, mRNA 3922 7890 pippin processing, RNA-binding, Nuclear proteinU79282 hypothetical protein Hypothetical protein 3923 7891 LOC137886U79290 Human clone 23908 3924 7892 mRNA sequence U79298 MGC39325hypothetical protein Hypothetical protein 3925 7893 MGC39325 U79458 WBP2Human WW domain Hypothetical protein 3926 7894 binding protein-2 mRNA,complete cds. U80628 TK2 thymidine kinase 2, Kinase, Transferase, DNAsynthesis, 3927 7895 mitochondrial ATP-binding, Mitochondrion, Transitpeptide, Alternative splicing U82277 LILRA2 leukocyte Immune response,Receptor, 3928 7896 immunoglobulin-like Repeat, Signal, Transmembrane,receptor, subfamily Immunoglobulin domain, B (with TM and ITIMGlycoprotein, Antigen, Alternative domains), member 1 splicing,Polymorphism, Multigene family, Phosphorylation, 3D-structure U83115AIM1 absent in melanoma 1 Repeat, Lectin 3929 7897 U90878 PDLIM1 PDZ andLIM Cytoskeleton, LIM domain, Metal- 3930 7898 domain 1 (elfin) binding,Zinc U90909 MISS chromosome 14 Hypothetical protein 3931 7899 openreading frame 32 U90911 WIRE WIRE protein 3932 7900 U90916sortilin-related Endocytosis, Receptor, 3933 7901 receptor, L(DLRTransmembrane, EGF-like domain, class) A repeats- Repeat, Glycoprotein,LDL, Lipid containing transport, Cholesterol metabolism, SignalW61000_RC NORE1 Ras association Hypothetical protein 3934 7902(RaIGDS/AF-6) domain family 5 X00437 IGHM Human mRNA for T-Immunoglobulin domain, 3935 7903 cell specific protein. Immunoglobulin Cregion, Glycoprotein, Repeat, Pyrrolidone carboxylic acid, Polymorphism,Membrane, Hypothetical protein, Receptor, T-cell, Signal X04201 TPM3tropomyosin 3 Hypothetical protein, Muscle protein, 3936 7904Cytoskeleton, Actin-binding, Coiled coil, Alternative splicing,Multigene family, Disease mutation X04526 GNB1 Human liver mRNATransducer, Repeat, WD repeat, 3937 7905 for beta-subunit Multigenefamily, 3D-structure signal transducing proteins Gs/Gi (beta- G). X07618CYP2D6 cytochrome P450, Heme, Monooxygenase, 3938 7906 family 2,subfamily Oxidoreductase, Electron transport, D, polypeptide 6 Membrane,Microsome, Endoplasmic reticulum, Polymorphism X13956 MGC10471hypothetical protein 3939 7907 MGC10471 X15183 HSPCA heat shock 90 kDaHeat shock, Chaperone, ATP- 3940 7908 protein 1, alpha binding,Phosphorylation, 3D- structure, Hypothetical protein, Plasmid X51630 WT1Wilms tumor 1 Zinc-finger, Metal-binding, DNA- 3941 7909 binding,Repeat, Nuclear protein, Transcription regulation, Alternative splicing,Anti-oncogene, Disease mutation, Chromosomal translocation, 3D-structureX52015 IL1RN interleukin 1 receptor Glycoprotein, Signal, Alternative3942 7910 antagonist splicing, 3D-structure X52882 TCP1 t-complex 1Chaperone, ATP-binding, Multigene 3943 7911 family X56789 TTS-2.2transport-secretion Hypothetical protein 3944 7912 protein 2.2 X57352IFITM3 interferon induced Interferon induction, 3945 7913 transmembraneTransmembrane protein 3 (1-8U) X58536 HLA-C major Glycoprotein, Signal,3946 7914 histocompatibility Transmembrane, Hypothetical complex, classI, C protein, MHC, MHC I, Polymorphism, 3D-structure, Alternativesplicing X58794 AZU1 azurocidin 1 Serine protease homolog, 3947 7915(cationic Glycoprotein, Chemotaxis, Antibiotic, antimicrobial proteinHeparin-binding, Signal, 3D- 37) structure X59417 PSMA6 proteasomeProteasome, Hydrolase, Protease, 3948 7916 (prosome, Threonine proteasemacropain) subunit, alpha type, 6 X61079 IGHM T cell receptorImmunoglobulin domain, 3949 7917 alpha-chain (TCR Immunoglobulin Cregion, Valpha20Jalpha9.14) Glycoprotein, Repeat, Pyrrolidone mRNA,partial cds. carboxylic acid, Polymorphism, Membrane, Hypotheticalprotein, Receptor, T-cell, Signal X62535 DGKA diacylglycerolHypothetical protein, Kinase, 3950 7918 kinase, alpha 80 kDaTransferase, Calcium-binding, Phorbol-ester binding, Repeat, Multigenefamily X63417 IRLB c-myc promoter- DNA-binding, Hypothetical protein3951 7919 binding protein X69115 ZNF37A zinc finger protein Hypotheticalprotein, Metal-binding, 3952 7920 37a (KOX 21) Nuclear protein, Zinc,Zinc-finger, Transcription regulation, DNA- binding, Repeat X71490ATP6V0D1 H. sapiens mRNA for Hydrolase, ATP synthesis, Hydrogen 39537921 vacuolar proton ion transport ATPase, subunit D. X78817 ARHGAP4 RhoGTPase GTPase activation, SH3 domain, 3954 7922 activating protein 4Coiled coil X87949 HSPA5 heat shock 70 kDa ATP-binding, Endoplasmicreticulum, 3955 7923 protein 5 (glucose- Signal regulated protein, 78kDa) X89214 hpr H. sapiens mRNA for Hydrolase, Protease, Serine 39567924 haptoglobin related protease protein. X94232 MAPRE2 microtubule-T-cell 3957 7925 associated protein, RP/EB family, member 2 X98258MPHOSPH9 M-phase Phosphorylation, Golgi stack, 3958 7926 phosphoprotein9 Membrane, Coiled coil X98261 ZWINTAS ZW10 interactor Phosphorylation,Nuclear protein, 3959 7927 Coiled coil X98411 MYO1F myosin IF Myosin,ATP-binding, Actin-binding, 3960 7928 Calmodulin-binding, SH3 domain,Multigene family Y00433 GPX1 glutathione Oxidoreductase, Peroxidase,3961 7929 peroxidase 1 Selenium, Selenocysteine, Erythrocyte,Polymorphism, Hypothetical protein Y00816 CR1 complement Complementpathway, Glycoprotein, 3962 7930 component (3b/4b) Transmembrane,Repeat, Signal, receptor 1, including Receptor, Sushi, Blood group Knopsblood group antigen, Polymorphism, Pyrrolidone system carboxylic acid,3D-structure Y14442 OR1F1 olfactory receptor, G-protein coupledreceptor, 3963 7931 family 1, subfamily Transmembrane, Glycoprotein, F,member 1 Multigene family, Olfaction Y18490 LST1 leukocyte specificImmune response, Cell shape, 3964 7932 transcript 1 Transmembrane,Alternative splicing Z15114 PRKCG protein kinase C, Transferase,Serine/threonine- 3965 7933 gamma protein kinase, ATP-binding,Calcium-binding, Metal-binding, Zinc, Repeat, Phorbol-ester binding,Phosphorylation, Polymorphism Z34893 IGHM Clone P2-114 anti-Immunoglobulin domain, 3966 7934 oxidized LDL Immunoglobulin C region,immunoglobulin Glycoprotein, Repeat, Pyrrolidone heavy chain Fabcarboxylic acid, Polymorphism, mRNA, partial cds Membrane, Hypotheticalprotein, Receptor, T-cell, Signal Z48314 MUC5AC mucin 5, subtypes ARepeat, Glycoprotein, Signal, 3967 7935 and C, Polymorphism,Hypothetical protein tracheobronchial/gastric Z49105 SSX2 synovialsarcoma, X Chromosomal translocation, Proto- 3968 7936 breakpoint 2oncogene, Multigene family, Transcription regulation

7. REFERENCES CITED

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

Many modifications and variations of the present invention can be madewithout departing from its spirit and scope, as will be apparent tothose skilled in the art. The specific embodiments described herein areoffered by way of example only, and the invention is to be limited onlyby the terms of the appended claims along with the full scope ofequivalents to which such claims are entitled.

What is claimed:
 1. A computer-implemented method for determining theresponsiveness of a chronic myeloid leukemia (CML) patient to imatinibmesylate (IM), comprising: (a) classifying, on a computer, a markerprofile comprising measurements of a plurality of gene products in acell sample taken from said patient as an IM-sensitive profile or anIM-resistant profile, wherein said gene products are respectivelyproducts of at least five of the genes listed in Table 4; (b)determining said patient as responsive to IM treatment if said markerprofile is classified as an IM-sensitive profile, or determining saidpatient as resistant to IM treatment if said marker profile isclassified as an IM-resistant profile; and (c) outputting to a user, auser interface device, a monitor, a computer readable storage medium, alocal computer, or a computer that is part of a network; or displaying;the determination resulting from step (b).
 2. The method of claim 1,wherein the gene products are products consisting of 5, 10, 15, 20, 25,30, 40, 60, 70, 80, 90, 100, 200, or 228 of the genes listed in Table 4.3. The method of claim 1, further comprising obtaining said markerprofile by a method comprising measuring said plurality of gene productsin a cell sample taken from said patient.
 4. The method of claim 3,wherein said cell sample is a sample from bone marrow or peripheralblood.
 5. The method of claim 1, wherein said classifying is carried outby a method comprising using a progression classifier, wherein saidprogression classifier receives an input comprising said marker profileand provides an output comprising data indicating whether said markerprofile is an IM-sensitive profile or an IM-resistant profile.
 6. Themethod of claim 1, wherein the gene products are selected from the groupconsisting of at least 5, 6, 7, or 8 of the genes selected from thegroup consisting of serine threonine kinases CTRL, MAP21K14, CLK3, MAPkinase MKNK2, tyrosine kinase oncogene FYN, TCF7, guanine nucleotidebinding proteins GNAZ and GNG11, and MAF.
 7. The method of claim 1,wherein each of said gene products is a gene transcript.
 8. The methodof claim 7, wherein measurement of each said gene transcript is obtainedby a method comprising contacting a positionally-addressable microarraywith nucleic acids from said cell sample or nucleic acids derivedtherefrom under hybridization conditions, and detecting the amount ofhybridization that occurs, said microarray comprising one or morepolynucleotide probes complementary to a hybridizable sequence of eachsaid gene transcript.
 9. The method of claim 7, wherein measurement ofeach said gene transcript is obtained by quantitative reversetranscriptase PCR (qRT-PCR).
 10. The method of claim 1, wherein each ofsaid plurality of gene products is a protein.
 11. The method of claim 1,wherein said classifying is carried out using a progression classifier,wherein said progression classifier receives an input comprising saidmarker profile and provides an output comprising data indicating whethersaid marker profile is a IM resistant profile or an IM responsiveprofile.
 12. The method of claim 11, wherein said step of classifying iscarried out by a method comprising (i) comparing said marker profilewith an IM resistant template profile and/or an IM responsive templateprofile, wherein said IM resistant template profile and IM responsivetemplate profile are obtained from a training population comprising IMresistant patients and IM responsive patients, respectively; and (ii)classifying said marker profile as an IM resistant profile if saidmarker profile has a high similarity to said IM resistant templateprofile and/or has a low similarity to said IM resistant templateprofile, or classifying said marker profile as an IM responsive profileif said marker profile has a high similarity to said IM responsivetemplate profile and/or has a low similarity to said IM resistanttemplate profile, wherein a high similarity corresponds to a degree ofsimilarity above a predetermined threshold, and wherein a low similaritycorresponds to a degree of similarity no greater than said predeterminedthreshold.
 13. The method of claim 11, wherein said step of classifyingis carried out by a method comprising (i) comparing said marker profilewith said IM resistant template profile or said IM responsive templateprofile; and (ii) classifying said marker profile as an IM resistantprofile if said marker profile has a high similarity to said IMresistant template profile or has a low similarity to said IM responsivetemplate profile, or classifying said marker profile as an IM responsiveprofile if said marker profile has a high similarity to said IMresponsive template profile or has a low similarity to said IM resistanttemplate profile, wherein a high similarity corresponds to a degree ofsimilarity above a predetermined threshold, and wherein a low similaritycorresponds to a degree of similarity no greater than said predeterminedthreshold.
 14. The method of claim 12, wherein said step of classifyingis carried out by a method comprising (i) comparing said marker profilewith said IM resistant template profile and said IM responsive templateprofile; and (ii) classifying said marker profile as an IM resistantprofile if said marker profile has a higher similarity to said IMresistant template profile than to said IM responsive template profile,or classifying said marker profile as a IM responsive profile if saidmarker profile has a higher similarity to said IM responsive templateprofile than to said IM resistant template profile.
 15. The method ofclaim 11, wherein said progression classifier is based on aclassification method selected from the group consisting of anartificial neural network, a support vector machine, logic regression,linear or quadratic discriminant analysis, decision trees, principalcomponent analysis, and nearest neighbor classifier analysis.